Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=3)=[C:9](OC)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([Mg]Br)[CH2:23][CH3:24].[Cl-].[NH4+]>O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=3)=[C:9]([CH2:22][CH2:23][CH3:24])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC[Mg]Br
Reactant: COc1cc(-c2ccccc2)ccc1C1=NC(C)(C)CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1cc(-c2ccccc2)ccc1C1=NC(C)(C)CO1
Temperature: 25 °C

Procedure:
2-(4-Phenyl-2-methoxyphenyl)-4,4-dimethyl-2-oxazoline (3.00 g) is dissolved in tetrahydrofuran (30 ml) under argon atmosphere, and the mixture is stirred with cooling over an ice-bath. To the mixture is added dropwise gradually an about 2M solution of 1-n-propylmagnesium bromide in tetrahydrofuran (8.0 ml) at the same temperature. After addition, the mixture is warmed to room temperature, and stirred for 16 hours. The reaction solution is stirred with cooling over an ice-bath, and thereto is added a saturated aqueous ammonium chloride solution (30 ml). The mixture is warmed to room temperature, and the organic layer is collected. The aqueous layer is extracted with ethyl acetate (30 ml×2), and the extract is combined with the organic layer, washed with a saturated aqueous sodium chloride solution (100 ml×2), dried over magnesium sulfate, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; dichloromethane:n-hexane=1:2→1:1), and evaporated to remove the solvent to give 2-(4-phenyl-2-n-propylphenyl)-4,4-dimethyl-2-oxazoline (2.81 g) as colorless transparent viscous oil.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[NH:43][C:44](=[O:70])[NH:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:60]=[C:59]3[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]3=[O:61])=[CH:54][CH:53]=2)=[CH:48][CH:47]=1>>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[NH:43][C:44](=[O:70])[NH:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:60]=[C:59]3[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]3=[O:61])=[CH:54][CH:53]=2)=[CH:48][CH:47]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4c(F)cccc4F)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4c(F)cccc4F)cc3)cc2C1=O
Yield: 90 %

Procedure:
The compound of example 20 was prepared analogous to compound of example 8 by hydrolysis of compound of example 19.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21]Br>CS(C)=O.O>[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[C:7]3([CH2:21][CH2:20][CH2:19]3)[C:6]=2[CH:5]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc2c(c1)C1(CCC1)c1cc(Br)ccc1-2
Reaction time: 120 h

Procedure:
Powdered KOH (983 mg, 17.5 mmol) was added in batches over 1 minute to a heterogeneous mixture of 2,7-dibromo-9H-fluorene (1.31 g, 4.04 mmol) and 1,3-dibromopropane (837 mg, 4.15 mmol) in DMSO (20 mL), and stirred at ambient condition for ˜5 days. The mixture was diluted with water (200 mL) and extracted with 10% CH2Cl2/hexanes (100 mL, 2×). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude material was purified with a column chromatography (sample was loaded as a silica gel mesh; hexanes, with gravity elution) to afford 2′,7′-dibromospiro[cyclobutane-1,9′-fluorene] as a white fluffy solid (600 mg). 1H NMR (CDCl3, δ=7.24, 400 MHz): 7.86 (d, J=1.8, 2H), 7.48 (d, J=8.0, 2H), 7.44 (dd, J=8.1, 1.8, 2H), 2.61 (app t, J=8.1, 4H), 2.42-2.34 (m, 2H).
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.[CH3:49][N:50]([CH3:56])[C@H:51]1[CH2:55][CH2:54][NH:53][CH2:52]1>CN(C)C=O>[CH3:49][N:50]([CH3:56])[C@H:51]1[CH2:55][CH2:54][N:53]([C:10]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:11])[CH2:52]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccn2)C1
Reaction time: 3 h
Yield: 54 %

Procedure:
To a solution of [4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added (3S)-3-dimethylaminopyrrolidine (0.050 ml) at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (23.0 mg, 54%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:8][CH:9]=1)(OC)=[O:2].[NH3:18]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:8][CH:9]=1)(=[O:2])[NH2:18]
Reactant: N
Reactant: COC(=O)c1c[nH]c(-c2ccc(OC)cc2)n1
Solvent: CO
Product: COc1ccc(-c2nc(C(N)=O)c[nH]2)cc1
Temperature: 1220 °C
Yield: 64.4 %

Procedure:
A mixture of 63 (21 g, 0.09 mol), CH3OH (700 ml) and NH3 (250 g) was heated in a sealed tube at 1220° C. for 24 hours. After washing out the contents, the suspension was concentrated to dryness and the residue crystallized from CH3OH to yield 12.6 g (64%) of 64.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9](Br)[CH2:10][CH2:11][CH3:12]>>[CH2:9]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCBr
Reactant: Oc1cccc(O)c1
Product: CCCCOc1cccc(O)c1
Yield: 39 %

Procedure:
Prepared according to the method described in Example A above from resorcinol (55 g; 0.5 mol) and n-butylbromide (75.4 g; 0.55 mol) to yield 32.4 g (39%) of the title compound as an oil (92% purity). bp 148° C. (12 mm Hg) MW=166 (GC-MS)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11][CH2:12][C:13]2[C:14]([C:19]3[N:23](C4CCCCO4)[N:22]=[CH:21][C:20]=3[CH3:30])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][N:10]=1)[CH:6]=[O:7].Cl>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11][CH2:12][C:13]2[C:14]([C:19]3[NH:23][N:22]=[CH:21][C:20]=3[CH3:30])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][N:10]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)c(OCc2cccnc2-c2c(C)cnn2C2CCCCO2)cn1
Agent: Cl
Solvent: CCO
Product: COc1cc(C=O)c(OCc2cccnc2-c2[nH]ncc2C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To 2-methoxy-5-((2-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (110 mg, 0.27 mmol, 1 equiv) suspended in EtOH (1 mL) was added HCl (1.0 mL, 3 N). The solution turned homogeneous and the mixture was stirred at rt overnight. The EtOH was partially removed by blowing in N2 gas and basified to pH 9. The aqueous solution was extracted with EtOAc three times. The organic layer was dried over Na2SO4 and concentrated. The crude was purified on silica gel using a mixture of MeOH and DCM as eluent to give 2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (40 mg, 46%) as a white solid. 1H NMR (400 MHz; CDCl3) δ=10.45 (s, 1H), 8.76 (d, 1H), 8.07 (br, 1H), 8.05 (s, 1H), 7.53 (s, 1H), 7.40 (dd, 1H), 7.13 (s, 1H), 5.52 (br, 2H), 3.98 (s, 3H). LRMS (MAT) m/z 325.1.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)#[N:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[CH3:26][C:27]([CH3:29])=O>>[CH3:26][C:27]1([CH3:29])[O:12][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=2[C:8](=[O:10])[O:9]1
Reactant: N#Cc1ccc(O)c(C(=O)O)c1
Reactant: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(C#N)ccc2O1
Reaction time: 20 h
Yield: 15 %

Procedure:
To a suspension of 5-cyano salicylic acid (60 g, 0.368 mol) in TEA (134 mL, 1.76 mol) and TFAA (45 mL, 0.32 mol) was added dry acetone (20 mL) and heated to reflux. After each 1 h interval was added 15 mL of dry acetone for 4 times and the reflux continued for 20 h. The reaction mixture was concentrated under vacuum and crude purified by flash column chromatography over silica gel (230-400 mesh) using CH2Cl2 as an eluent to give the title compound as a white solid (12 g, 15%). TLC: CH2Cl2 (100%), Rf: 0.5
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:19]1[CH2:24][CH2:23]N(S(C2C=CC(C#N)=CC=2)(=O)=O)[CH2:21][CH2:20]1.S.BrCC(=O)C(OCC)=O>>[N:1]1([S:2]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=3)=[CH:9][CH:10]=2)(=[O:3])=[O:4])[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: NS(=O)(=O)c1ccc(-c2nc(C(=O)O)cs2)cc1
Agent: CCOC(=O)C(=O)CBr
Agent: S
Product: O=C(O)c1csc(-c2ccc(S(=O)(=O)N3CCOCC3)cc2)n1

Procedure:
In a manner similar to that described for the preparation of 2-(4-aminosulfonylphenyl)thiazole-4-carboxylic acid, 460 mg of 4-(morpholinosulfonyl)-benzonitrile was treated with H2S, ethyl bromopyruvate, and LIOH successively to give the title compound. MS m/z: 355 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[O:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:34][CH2:33]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CC1CCNCC1
Product: CC1CCN(CCc2cc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)ccc3o2)CC1

Procedure:
The product from Example 23D and 4-methyl piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.75 (d, J=8.1, 2H), 7.58 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.76 (s, 1H), 3.35-3.8 (m, 14H), 3.05 (m, 2H), 2.00 (m, 2H), 1.75 (m, 1H), 1.49 (m, 2H), 1.05 (d, J=6.6 Hz, 3H); MS (DCI) m/z 433 (M+H)+;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)C>C1COCC1>[OH:15][CH2:14][C:11]1([CH3:17])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Solvent: C1CCOC1
Solvent: CSC
Product: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 99.1 %

Procedure:
A suspension of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.750 g, 3.08 mmol) in THF (5 mL) at rt under N2 was treated with 2M THF solution of BH3 SMe2 (1.541 mL, 3.08 mmol). After 18 h, the reaction was cooled in an ice bath and quenched by the addition of 5 mL of 1N NaOH. Partitioned between ether and water. Organic phase dried (MgSO4), filtered, and concentrated in vacuo to give 700 mg (99%) of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.86-3.64 (m, 3H), 3.41 (s, 2H), 3.15 (ddd, J=13.6, 10.2, 3.5 Hz, 2H), 1.94-1.80 (m, 1H), 1.52-1.43 (m, 10H), 1.31 (dt, J=13.5, 3.8 Hz, 2H), 1.01 (s, 3H).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15]C(=O)OC(C)(C)C)[CH2:12][C@H:11]2[CH2:13][CH3:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1>Cl.O1CCOCC1>[NH2:15][C@:10]1([C:8]([NH:7][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])=[O:9])[CH2:12][C@H:11]1[CH2:13][CH3:14]
Reactant: CC[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Tert-butyl (1R,2R)-1-(cyclopropylsulfonylcarbamoyl)-2-ethylcyclopropylcarbamate (0.53 g, 1.60 mmol) was dissolved in 4 N HCl in dioxane (20 mL) and stirred at rt for 5 hour. Removal of solvent gave (1R,2R)-1-amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamide dihydrchloride as a white foamy solid. It was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH2:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH3:20]>CC(C)=O.CN(C=O)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([N:21]([C:16]2[S:15][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:17]=2)[CH2:19][CH3:20])=[CH:23][CH:24]=1
Reactant: N#C[S-]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCNc1ccc(Br)cc1
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: CCN(c1ccc(Br)cc1)c1nc(=O)c2cccnc2s1
Yield: 75.3 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.203 g (7.63 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 639 mg of ammonium thiocyanate, 15 ml of acetone, 1.53 g of N-ethyl-4-bromoaniline and 10 ml of acetone were used. The product was then recrystallized from ethanol to obtain 2.08 g of 2-[N-(4-bromophenyl)-N-ethylamino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.CO>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:12]2[N:11]=[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=2)[CH2:20][CH2:21]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(Nc2cc(N(C)C)nc(N3CCN(Cc4ccccc4)CC3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
A mixture of N4-(3-methoxyphenyl)-N6,N6-dimethyl-2-(1-piperazinyl)-4,6-pyrimidinediamine (36 mg, 0.10 mmol) and benzaldehyde (11 mg, 0.1 mmol) in a solution of methanol (5 mL) and acetic acid (0.5 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (7 mg, 0.1 mmol) was added to the above solution and stirred at room temperature for 16 h. The crude product was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). The organic layer washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (8 mg, 40%).
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1.[OH-:11].[Na+]>CO>[C:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[C:1]([NH2:10])=[O:11])#[N:6]
Reactant: N#Cc1cccc(C#N)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(C(N)=O)c1
Yield: 89.6 %

Procedure:
Isophthalonitrile (12.8 g, 0.1 mol) and methanol (115.2 g) were mixed, and the resultant mixture was heated to 64° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (10 g) was added over six hours. Liquid chromatographic analysis revealed the reaction mixture contained 13.1 g of m-cyanobenzamide (yield 90%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]1[C:31]([SH:32])=[N:30][N:29]=[N:28]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:32][C:31]3[N:27]([CH3:26])[N:28]=[N:29][N:30]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nnnc1S
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cn1nnnc1SCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 70 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 1-methyl-5-mercaptotetrazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 70% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]CC)=O.[CH2:11]([Mg]Br)[CH3:12].[CH2:15](OCC)[CH3:16]>>[OH:8][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([CH2:11][CH3:12])[CH2:15][CH3:16]
Reactant: CCOC(=O)c1cccs1
Reactant: CC[Mg]Br
Reactant: CCOCC
Product: CCC(O)(CC)c1cccs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a stirred 0° C. mixture of ethyl thiophene-2-carboxylate (3.12 g, 20.0 mmol) in diethyl ether (100 ml) is added 1M ethylmagnesium bromide (60 ml, 60 mmol). The reaction is allowed to warm to RT and stirred for 3 d. The reaction is partitioned between Et2O and 1N NaHCO3. The organic layer was Na2SO4 dried and concentrated to give the title compound (3.4 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=1)=[O:5])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]([N+:19]([O-:21])=[O:20])[N:8]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Nc1ccc(NC(=O)OCC)nc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Nc1ccc(NC(=O)OCC)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
40 ml of concentrated sulphuric acid are cooled to 8° C. and 5 g of the compound of Stage 1 are added while stirring. At 5° C., 5 ml of concentrated nitric acid are then added dropwise and stirring is continued for 1 hour. Subsequently the mixture is poured on 300 to 400 g of ice and the precipitated crystals are isolated by filtering with suction 4 g of a yellow crystalline compound are obtained. On recrystallizing from ethanol this compound melts at 193° C. 1H-NMR Spectrum: 10.38 (s, NH), 9.72 (s, NH), 8.23 (d, J=9 Hz, 4-H), 8.10 (d, J=9 Hz, 3-H), 4.19d (q, J=7 Hz, OCH2), 4.13 (q, J=7 Hz, OCH2), 1.25 (t, J=7 Hz, CH3), 1.23 (t, J=7 Hz, CH3)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH2:11][CH2:12]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and acetyl chloride (0.023 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give N-(1-acetylpiperidin-4-yl)-2-(2,4-dichlorophenoxy)benzamide (84 mg, 75%) as an oil. Rf: 0.15 (EtOAc) LC/MS (APCI) tr=3.78 min, m/z 409.31 (67), 407.36 (M++H, 100). HPLC tr=2.69 min (96.74%) 1H NMR (270 MHz, CDCl3) δ 1.38 (2H, m, CH2), 2.00 (2H, m, CH2), 2.08 (3H, s, CH3), 2.84 (1H, m, ½CH2), 3.74 (1H, m, ½CH2), 4.18 (1H, m, CH), 4.41 (1H, m, ½CH2), 6.79 (1H, dd, J=8.2, 1.0 Hz, ArH), 6.88 (1H, d, J=8.6 Hz, ArH), 7.22 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.26 (1H, m, ArH), 7.37 (1H, br s, NH), 7.41 (1H, m, ArH), 7.51 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.9, 1.7 Hz, ArH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:2]=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=1.C(O)(=O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH:15][C:16]3[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=3)=[CH:9][CH:8]=2)[CH:2]=1
Reactant: COC(=O)c1cnc(N)s1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(NCc2ccc(-c3cccnc3)cc2)s1
Temperature: 0 °C

Procedure:
In a 250 mL round-bottomed flask was added 4-(pyridin-3-yl)benzaldehyde (4 g, 21.83 mmol), methyl 2-aminothiazole-5-carboxylate (3.45 g, 21.83 mmol), and acetic acid (0.375 ml, 6.55 mmol) in toluene (109 ml). The mixture was heated at reflux under Dean-Stark conditions for 3 hours, cooled, concentrated and redissolved in methanol. The mixture was cooled to 0° C. and sodium borohydride (1.322 g, 34.9 mmol) was carefully added. The mixture was warmed to room temperature and the resulting suspension was filtered with water washes to provide the title compound after drying.