Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[N:14][CH3:15])[CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])C.[C:16]([NH2:22])(=[O:21])[C:17]([NH:19][NH2:20])=O.N>CN1CCOCC1.ClCCl>[F:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([F:13])[C:6]=1[CH2:5][C:4]1[N:14]([CH3:15])[C:17]([C:16]([NH2:22])=[O:21])=[N:19][N:20]=1
Reactant: CCOC(Cc1c(F)cccc1F)=NC
Reactant: NNC(=O)C(N)=O
Agent: N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cn1c(Cc2c(F)cccc2F)nnc1C(N)=O

Procedure:
320 mg (1.5 mmol) of 1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane and 155 mg (1.5 mmol) of oxalic acid monoamide monohydrazide are dissolved under a nitrogen atmosphere in 5 ml of N-methylmorpholine and the whole is heated under reflux for 41 hours. After cooling, the reaction mixture is diluted with 20 ml of dichloromethane and extracted by shaking in succession twice with water, twice with 2N hydrochloric acid and again with water The last three acidic aqueous phases obtained are combined, rendered alkaline with concentrated ammonia solution and extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulphate and concentrated. Recrystallisation of the crude product from ethanol yields 102 mg (27% of the theoretical yield) of the desired 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide which melts at 189°-190°.
Reaction SMILES: [CH:1]1([CH2:7]C2CCCCN2CC(C2C=CC=C(Br)C=2)C)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.C([Li])CCC.C([O:31][CH2:32][CH3:33])C>>[CH3:7][C:1]1[CH:6]=[CH:5][C:33]([CH:32]=[O:31])=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: CC(CN1CCCCC1CC1CCCCC1)c1cccc(Br)c1
Agent: [Li]CCCC
Product: Cc1ccc(C=O)cc1

Procedure:
Following a procedure similar to that described in Example 3, 18.9 g. (0.05 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was reacted with 0.1 mole of n-butyl lithium in diethyl ether and the resulting lithio derivative reacted directly with 12.3 g. (0.103 mole) of 4-methylbenzaldehyde to give 16.9 g. of 2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methylbenzyl)phenyl]propyl}piperidine as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[F:29][C:30]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:33]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc(F)cc3F)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2,4-difluorobenzoyl chloride: ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Temperature: 110 °C

Procedure:
A 10-20 mL microwave vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (503 mg, 1.098 mmol), pyrimidin-5-ylboronic acid (143 mg, 1.153 mmol), tetrakis(triphenylphosphine)palladium (127 mg, 0.110 mmol). The vial was flushed with Ar(g), then THF (5489 μL, 1.098 mmol) and potassium carbonate (1.5 M) (1464 μL, 2.195 mmol) (aq. solution) were added in sequence. The vial was sealed and heated at 110° C. for 2 hours. The mixture was diluted with water and extracted with 10% i-PrOH/EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 100-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to provide (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=[O:7].[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[F:1])[CH2:9][CH3:10])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1ccccc1F)C(=O)O
Product: CCC(Oc1ccccc1F)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 98 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.72 g of (2RS)-2-(2-fluorophenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.30 g of the title compound as a colorless foam.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:54]([NH:64][C@H:65]([C:67](O)=[O:68])[CH3:66])([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55]>>[C:54]([NH:64][C@H:65]([C:67]([NH:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:68])[CH3:66])([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](N)CC(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1

Procedure:
from N-(2-L-leucyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-octadecanamide and N-carbobenzoxy-L-alanine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-])=O)=[C:14]([F:19])[CH:13]=[C:12]([F:20])[C:11]=1[F:21].[Cl-].[NH4+].CCOC(C)=O>CCO.[Fe]>[F:21][C:11]1[C:12]([F:20])=[CH:13][C:14]([F:19])=[C:15]([NH2:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Yield: 66.4 %

Procedure:
To the stirred solution of (2-fluoro-4-iodo-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine 3 (5.2 gm, 12.62 mmol) in EtOH (200 ml), ammonium chloride (10.12 gm, 189.3 mmol) and iron powder (10.57 gm, 189.3 mmol) was added. This reaction mixture was kept stirring at reflux for 16 hours. Reaction mixture was allowed to cool and was filtered over celite and concentrated to dryness. The residue obtained was taken into EtOAc and was washed with water. The EtOAc layer was dried over sodium sulfate and further purified by crystallization from EtOH to provide off-white solid (3.2 gm, yield: 66.39%). M−H+: 381.1. 1H NMR (DMSO, 300 MHz): 5.0 (s, 2H); 6.2 (t, 1H); 7.2-7.3 (m, 2H); 7.45 (s, 1H); 7.5 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1.[Na].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1)[CH3:22]
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Reactant: CCO
Agent: [Na]
Product: CCOc1nc2ncnn2c2c1cnc1c2cnn1CC

Procedure:
2.7 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine of Example 1 (b) (0.01 mol.) are added with stirring to a solution of 2.3 g. of sodium in 50 ml. of dry ethanol. The mixture is stirred at room temperature for 6 hours. The precipitate is filtered off, washed with water and recrystallized from ethanol to obtain 5-ethoxy-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine, yield 2.1 g. (74%); m.p. 196°-197°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13](Cl)=[O:14])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH2:25][CH3:26])=[N:10][CH:9]2[CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([C:13]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:14])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH2:25][CH3:26])=[N:10][CH:9]2[CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.1 %

Procedure:
A solution of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (50 mg, 0.105 mmol) in methylene chloride (2 mL) was added to a stirred mixture of 1-methylpiperazine (18 μL, 0.158 mmol) and triethylamine (29 μL, 0.210 mmol) in methylene chloride (3 mL) cooled to 0° C. The reaction mixture was stirred at room temperature for 30 min then concentrated in vacuo. Purification of the crude residue by preparative HPLC (Zorbax C18) gave [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (64 mg, 93%, white solids) as trifluoroacetic acid salt. HR-MS (ES, m/z) observed 539.2789, calculated for C30H40N4O3Cl [(M+H)+]539.2784.
Reaction SMILES: O.[ClH:2].[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([C:15]([CH3:17])=[O:16])([CH3:14])=[O:13].C(O)(C)C.O.C([O-])(=O)C.[Na+]>O>[ClH:2].[CH3:17][C:15]1([OH:16])[C:12]([CH3:14])([OH:13])[NH:11][C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:10]1
Reactant: N=C(N)c1ccccc1
Reactant: CC(=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC1(O)N=C(c2ccccc2)NC1(C)O
Reaction time: 4 h

Procedure:
To 56.4 g (0.323 mole) of benzamidine hydrochloride hydrate in 200 ml of warm water is added with vigorous stirring 40 ml of biacetyl. Within a few minutes a heavy precipitate forms and 150 ml of isopropyl alcohol is added followed by 5.0 g of sodium acetate hydrate dissolved in 15 ml of warm water. Stirring is continued for 4 hours after which time the product, 4,5-dimethyl-2-phenylimidazoline-4,5-diol hydrochloride, is filtered off and washed with isopropyl alcohol. Recrystallization from 95% ethanol gives the pure product, m.p. 162°-165° C (dec.).
Reaction SMILES: [CH2:1]([OH:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:10][C:11]([CH3:13])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:10][C:11]1([CH3:13])[O:9][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: CC(C)=O
Reactant: OCc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)OCc2ccccc2O1

Procedure:
First the hydroxyl groups of Salicyl alcohol were protected with acetone in refluxing benzene with the catalysis of para-toluenesulfonic acid to give 2,2-Dimethyl-4H-benzo[1,3]dioxine in quantitive yield. Friedel-craft acylation of this compound with AlCl3 and acetyl chloride in refluxing chloroform afforded 1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-ethanone in good yield. This was further brominated in chloroform with the catalysis of benzoyl peroxide to give 2-bromo-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-ethanone, which was reduced to the chiral or nonchiral bromohydrine with borane and borane/oxazaborolidine, respectively. The title epoxide was generated by the addition of the above bromohydrine to a suspension of NaH in THF, as described previously.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:13]([OH:22])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH2:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Si:23]([O:40][CH2:41][C:42]([CH3:46])([CH3:45])[CH:43]=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C(O)(=O)C>[C:3]1([CH:13]([OH:22])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH:21][CH2:43][C:42]([CH3:46])([CH3:45])[CH2:41][O:40][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Nc1ccc(Cl)cc1C(O)c1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(CNc1ccc(Cl)cc1C(O)c1cccc2ccccc12)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57.4 %

Procedure:
Sodium borohydride (1.73 g, 45.8 mmol) was added portionwise to a solution of α-(1-naphthyl)-2-amino-5-chlorobenzyl alcohol (9.76 g, 34.4 mmol) and 3-tert-butyldiphenylsilyloxy-2,2-dimethylpropanal (12.89 g, 37.9 mmol) in acetic acid (105 ml) at 0° C. The reaction mixture was allowed to warm to room temperature, and stirring was continued for 45 min. Hydrolysis with water was followed by repeated extraction of the mixture with ethyl acetate. The combined organic layers were washed with 1 N sodium hydroxide and dried with MgSO4. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (hexane/ethyl acetate 9:1) to give the title compound (12.01 g, 57%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].Cl.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[N:29]1([C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:14][CH2:13]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:26])[CH2:32][CH2:31][CH2:30]1
Reactant: C1CNC1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: Cl
Agent: [Li+]
Product: O=C(c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1)N1CCC1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and azetidine hydrochloride (84 mg, 0.90 mmol). Yield: 41 mg (47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([Br:1])[CH:3]=2)[CH2:11][CH2:10]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2cccc(Br)c2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2cccc(Br)c2)CC1)c1ccccc1
Yield: 53.4 %

Procedure:
0.108 g (0.0004 mol) of 1-(3-bromo-benzyl)-piperidin-4-ol and 0.12 ml (0.00085 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.058 ml (0.0005 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.08 g (53.5%) of 1-(3-bromo-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil.
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].[CH:20]([C:22]1[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:24][CH:23]=1)=O.CO>COCCOC>[C:11]([CH2:20][C:22]1[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:24][CH:23]=1)#[N:12]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CS(=O)(=O)Nc1ccc(C=O)c2ccoc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: CS(=O)(=O)Nc1ccc(CC#N)c2ccoc12
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
A solution of tosylmethyl isocyanide (1.8 g, 9.22 mmole) in anhydrous ethylene glycol dimethyl ether (60 mL) was added drop-wise into a stirred suspension of potassium tert-butoxide (2.81 g, 25.0 mmole) in anhydrous ethylene glycol dimethyl ether (60 mL) under nitrogen at −65° C. After stirring at −65° C. for 15 min., N-(4-formyl-benzofuran-7-yl)-methanesulfonamide (2.0 g, 8.36 mmole) in anhydrous ethylene glycol dimethyl ether (60 mL) was added drop-wise and the reaction temperature was maintained below −60° C. After stirring for another hour before methanol (30 mL) was added. The reaction mixture was heated to reflux for 20 minutes then stirred at room temperature for 16 hrs. The resulting solution was partitioned between ethyl acetate and aqueous 2% acetic acid. The organic extract was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 40 to and 50% ethyl acetate in hexane to give N-(4-cyanomethyl-benzofuran-7-yl)-methanesulfonamide as a solid (1.31 g, 62%). 1H NMR (DMSO-d6) δ: 3.11 (s, 3H), 4.28 (s, 2H), 7.17 (d, 1H, J=2.2 Hz), 7.24-7.30 (m, 2H) 8.15 (d, 1H, J=2.2 Hz), 9.23 (s, 11H) M−H 249.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:30][CH3:31])[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.2 %

Procedure:
To a solution of 0.225 gm (0.77 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 20 mL acetonitrile were added 0.223 gm (1.617 mMol) potassium carbonate followed by 130 μL (1.617 mMol) iodoethane and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then heated at 60° C. for 4 hours and then at 50-45° C. for 3 hours. The reaction mixture was then concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic phase was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 2 mm), eluting with 97:3:1 dichloromethane: methanol:ammonium hydroxide. Fractions shown to contain the desired compound were concentrated under reduced pressure to give 0.045 gm (6%) of the desired compound. Exact Mass: Calculated for: C21H25N2O: Theory: 321.1967; Found: 321.1970.
Reaction SMILES: [SH:1][C:2]1[N:7]=[N:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1>CN(C=O)C>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH2:16][CH2:15][CH2:14][S:1][C:2]1[N:7]=[N:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(S)nn1
Reactant: FC(F)(F)c1cccc(OCCCCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=S)c1ccc(SCCCCOc2cccc(C(F)(F)F)c2)nn1
Temperature: 25 °C

Procedure:
A mixture of intermediate 11 (0.017 mol) in DMF (80 ml) was stirred at room temperature. Sodium hydride (50%, 0.02 mol) was added portionwise. The mixture was stirred for 30 minutes. A mixture of 1-(4-chlorobutoxy)-3-(trifluoromethyl)-benzene (0.02 mol) in DMF (20 ml) was added dropwise. The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was stiffed in DIPE (100 ml), filtered off and dried, yielding 3.lg (47%) of 6-[[4-[3-(trifluoromethyl)-phenoxy]butyl]thio]-3-pyridazinecarbothioamide (intermediate 12).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12]2>C(Cl)(Cl)Cl>[Br:6][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][CH:16]=1
Reactant: Brc1cccc2c1CCCC2
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.6 %

Procedure:
Chlorosulfonic acid (13.80 g, 7.93 ml, 118.00 mmol was added dropwise to a stirred solution of 5-bromo-1,2,3,4-tetrahydronaphthalene (prepared according to the procedure reported in the literature, WO2004/000792, 10.0 g, 47.4 mmol) in 50 ml chloroform at 0° C. The reaction mixture was then allowed to warm to about 25° C. and was stirred at the same temperature for 45 min. The progress of the reaction was monitored by TLC. The reaction mixture was then poured in ice-water (50 ml) and the mixture so obtained was extracted with chloroform (2×150 ml). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain the title compound (12.0 g, 81.6%), which was taken ahead as such without further purification for the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.[N-:27]=[N+:28]=[N-:29].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[N:4]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([C:23]4[N:27]=[N:28][NH:29][N:24]=4)=[CH:25][CH:26]=3)[N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1cc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)ccc1-c1nn[nH]n1
Temperature: 120 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzonitrile (11 mg, 0.031 mmol), sodium azide (5.5 mg, 0.085 mmol) and triethylamine hydrochloride (6.0 mg, 0.043 mmol) in 2 mL of DMF was stirred at 120° C. for 6 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give 2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine. Yield 12 mg, 97% yield; HPLC: Rt=2.09 min; MS 394 [M−H].