Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[N:10][C:9](=[O:12])[N:8]([CH2:13][CH:14]=O)[C:7]=2[CH:16]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[N:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:17]3[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]3)[C:7]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2nnc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2nnc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 34 %

Procedure:
A mixture of [6-(methyloxy)-3-oxo-1,2,4-benzotriazin-4(3H)-yl]acetaldehyde (as the methyl hemiacetal) (89 mg, 0.346 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (69 mg, 0.346 mmol) in chloroform (5 ml) and MeOH (0.5 ml) was stirred for 2 h before addition of NaBH(OAc)3 (220 mg, 1.038 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (20 ml). The reaction was then extracted with 20% MeOH in DCM (3×100 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-5% MeOH/DCM gradient to provide the desired compound (48 mg, 34%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([O:26][CH2:27][CH3:28])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[C:19]([O:26][CH2:27][CH3:28])[CH:18]=1
Reactant: CCOc1cc(Cl)ccc1B(O)O
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: CCOc1cc(Cl)ccc1-c1c(-c2cc(C#N)ccn2)ncn1C

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-2-ethoxyphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H15ClN4O, 340. Found, 339, 341.
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[CH:27]=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C@@H:17]([OH:31])[CH2:16][CH2:15]1)(C)(=O)=O.[Br-].C[Si](C)(C(C)(C)C)OCCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:65]([S:70][CH2:71][CH2:72][CH2:73][SH:74])[CH2:66][CH2:67][CH2:68][CH3:69]>>[CH2:65]([S:70][CH2:71][CH2:72][CH2:73][S:74][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[CH:27]=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C@@H:17]([OH:31])[CH2:16][CH2:15]1)[CH2:66][CH2:67][CH2:68][CH3:69]
Reactant: CCCCCSCCCS
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCOS(C)(=O)=O)[C@H]3[C@@H]1CC[C@@H]2O
Agent: CC(C)(C)[Si](C)(C)OCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCSCCCSCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
The process described in Example 32 was repeated using 7α-(6-mesyloxyhexyl)oestra-1,3,5(10)-triene-3,17β-diol (obtained as described in Example 41 using initially 5-(dimethyl-t-butylsilyloxy)pentyltriphenylphosphonium bromide and 3-n-pentylthiopropanethiol (obtained from trimethylene-1,3-dithiol and pentyl bromide) as starting materials. There was thus obtained as an oil 7α-[6-(3-n-pentylthiopropylthio)hexyl]-oestra-1,3,5(10)triene-3,17β-diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][N:5]2[C:6](=[O:13])[C:7]([C:10]([OH:12])=O)=[CH:8][N:9]=[C:4]2[CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:33][C:10]([C:7]2[C:6](=[O:13])[N:5]3[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][C:4]3=[N:9][CH:8]=2)=[O:12])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCC1
Reactant: Cc1ccn2c(=O)c(C(=O)O)cnc2c1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccn2c(=O)c(C(=O)NC3CCCC3)cnc2c1
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A mixture containing 1.22 g (0.006 mol) of 8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 0.84 ml (0.006 mol) of triethylamine in 40 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 0.46 ml (0.006 mol) of methyl chloroformate in 3 ml of chloroform is dropped to the above mixture at -15° C. during 10 minutes. After stirring for 5 minutes, 0.56 g (0.0066 mol) of cyclopentylamine dissolved in 6 ml of chloroform is dropped to the above solution. The reaction mixture is stirred at -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 15 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 15 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 0.9 g (55%) of the named compound as a crystalline substance after recrystallization from ethanol, m.p.: 220°-222° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])/[CH:5]=[CH:6]/[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[Br:13]Br.C(N(CC)CC)C>>[CH2:1]([O:3][C:4](=[O:12])/[C:5](/[Br:13])=[CH:6]/[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)/C=C/C1CCCC1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(Br)=C/C1CCCC1
Yield: 65 %

Procedure:
Following the method of example 54b, reaction of (E)-3-cyclopentyl-acrylic acid ethyl ester (87 g, 520 mmol) with bromine (29.3 ml, 572 mmol) and triethylamine (90 ml, 650 mmol) affords the title product as an oil (83.5 g) GC-MS (m/e): 247 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:16]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=[S:18])[NH:7][C:6]=2[CH:16]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2cscc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=C1Nc2cc(Cl)ccc2Nc2cscc21
Reaction time: 18 h

Procedure:
A mixture of 0.88 g. of 7-chloro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 1.0 g. of phosphorus pentasulfide in 10 ml. of dry pyridine is stirred and heated under reflux for 4 hours. The mixture is concentrated to dryness and the residue is stirred in 20 ml. of 1 N sodium carbonate solution (pH 7-7.2) for 18 hours. The precipitate is collected, washed with water and recrystallized from methanol-water to give a deep yellow solid, m.p. 197°-198.5° C. (dec.).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([C:11](=[O:15])[CH:12]([OH:14])[CH3:13])[CH:7]=[CH:8][C:9]=1[F:10].[C:16](O)(=[O:18])C.[C:20](O)(=O)C.IC1C=CC=CC=1>CO>[CH3:20][O:15][C:11]([O:18][CH3:16])([C:6]1[CH:7]=[CH:8][C:9]([F:10])=[C:4]([F:3])[CH:5]=1)[CH:12]([OH:14])[CH3:13]
Reactant: CC(O)C(=O)c1ccc(F)c(F)c1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Ic1ccccc1
Product: COC(OC)(c1ccc(F)c(F)c1)C(C)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a round bottom flask containing 200 mL of MeOH was added pellets of potassium hydroxide (23.0 g, 410.0 mmol). The solution was cooled to 0° C. and 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one (7.0 g, 41.2 mmol) in 10 mL MeOH was added dropwise. The solution was stirred for 10 min and then iodobenzene diacetate (22.5 g, 70 mmol) was added in two portions. The solution first became orange and then turned yellow. It was stirred overnight at room temperature and then solvent was removed in vacuo. The residue was dissolved in water and was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine and then dried over Na2SO4. After filteration, the solvent was removed in vacuo to get 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one dimethyl acetal as a yellow viscous oil (crude wt.=9.2 g). It was dissoled in 150 mL of acetone and 10 drops of concentrated sulfuric acid were added. After stirring for 3 h, TLC analysis indicated that the reaction was complete. Acetone was removed in vacuo and after basification with saturated NaHCO3, the residue was extracted in EtOAc and was washed with brine. The organic layer was separated, dried over Na2SO4 and then filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (Rf=0.4, 3:2 hexane/EtOAc) to obtain 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one as a pale yellow oil (3.3 g, 51% yield over two steps).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1.[H-].[Na+].[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31].O>C1COCC1>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:4]2[N:3]=[C:2]3[NH:1][C:30](=[O:31])[NH:10][C:8](=[O:9])[C:7]3=[CH:6][N:5]=2)=[N:12]1
Reactant: NC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c(=O)c2cnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2[nH]1
Reaction time: 0.42 h

Procedure:
70 mg (0.19 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-carb oxamide (example 104A) were initially charged in 7 ml of THF and, while cooling with ice, 30.8 mg (0.77 mmol) of sodium hydride (60% in mineral oil) were added over a period of 5 min. The mixture was stirred for 25 min, then 46.9 mg (0.29 mmol) of 1,1′-carbonyldiimidazole were added with ice cooling over 5 min. Conversion was effected at room temperature for 1 h and at reflux temperature for 90 min. After cooling, the mixture was hydrolyzed with 2 ml of water. The precipitate formed was filtered off and then stirred in 7 ml of methanol/water (5/2). The remaining precipitate was filtered off and dried under high vacuum. Thus, 26 mg (35% of theory) of the target compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:3]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=3[NH:1][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3cc(Cl)ccc3N)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 71.1 %

Procedure:
A mixture of tert-butyl 4-[4-(2-amino-5-chlorophenoxy)phenyl]piperazine-1-carboxylate (3.8 g, 9.5 mmols), ethyl 4-bromobutyrate (2.7 ml, 19 mmols), potassium carbonate (1.3 g, 9.5 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 72 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[4-(4-tert-butoxycarbonyl-1-piperazinyl)phenoxy]-4-chlorophenyl]aminobutyrate (3.5 g, 71%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH2:39]([N:41]1[C:53]2[CH:52]=[CH:51][C:50]([CH:54]=[O:55])=[CH:49][C:48]=2[C:47]2[C:42]1=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40]>>[CH2:39]([N:41]1[C:53]2[CH:52]=[CH:51][C:50]([CH:54]([OH:55])[C:35]3[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=3)[C@@H:8]3[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]3[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])=[CH:49][C:48]=2[C:47]2[C:42]1=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Product: CCn1c2ccccc2c2cc(C(O)c3cn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c(=O)[nH]c3=O)ccc21

Procedure:
5-((9-Ethylcarbazol-3-yl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 9-ethyl-3-carbazolecarboxaldehyde instead of benzophenone) as a yellow foam.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1>C(O)C>[CH:1]([C@H:14]1[CH2:20][C@H:19]([OH:18])[C@@H:17]([NH:30][CH2:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:16][O:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Reactant: NCCc1ccc(F)cc1
Solvent: CCO
Product: O[C@H]1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCCc1ccc(F)cc1

Procedure:
(1R,4R,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28c (0.02 g, 0.075 mmol) was reacted with 2-(4-fluorophenyl)-ethylamine (0.21 g, 1.50 mmol) in ethanol (Procedure E) to yield (2R,4S,5S)-2-benzhydryl-5-[2-(4-fluorophenyl)-ethylamino]-tetrahydropyran-4-ol, (+)-29c, 0.030 g (98%, [α]D=(+)63.4, c=1, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34]([CH3:36])=[N:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][C:34]1[NH:33][C:32]2[C:37]([CH3:39])=[CH:38][C:29]([NH:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:30][C:31]=2[N:35]=1
Reactant: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2[nH]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5[nH]c(C)nc5c4)ncn3)CC1)C(=O)N2

Procedure:
265 mg (0.962 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 250 mg (0.913 mmol) (6-chloro-pyrimidin-4-yl)-(2,7-dimethyl-1H-benzimidazol-5-yl)-amine and 1.00 mL (5.81 mmol) DIPEA were refluxed in 1.5 mL DMF. After the reaction had ended the reaction mixture was diluted with some DMF and microfiltered. The filtrate was purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([OH:21])[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([O:21][C:22](=[O:24])[CH3:23])[CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC1CC2(CCN(Cc3ccccc3)C2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(=O)OC1CC2(CCN(Cc3ccccc3)C2)c2ccccc21

Procedure:
56.0 g of 1'-benzyl-3-hydroxyspiro[indan-1,3'-pyrrolidine] are stirred at room temperature with 120 cc of pyridine and 120 cc of acetic anhydride for 20 hours. The mixture is then poured on ice, is made alkaline with 2 N caustic soda solution and is extracted thrice with 250 cc amounts of ether. The ether phase is washed with water, dried over sodium sulphate and concentrated by evaporation. 1'-Benzyl-3-acetoxyspiro[indan-1,3'-pyrrolidine] is obtained as light yellow oil, which is used for the next reaction without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:4][CH:3]=1.[CH3:17][S:18](C)=O.C[S-].[Na+].CCCCCCC>C(OCC)(=O)C>[CH3:17][S:18][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: Oc1ccccc1CNc1cccc(Cl)n1
Agent: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CSc1cccc(NCc2ccccc2O)n1
Temperature: 90 °C

Procedure:
Introduced into a microwave tube are 300 mg (1.28 mmol) of 2-[(6-chloropyridin-2-ylamino)methyl]phenol, to which 5 ml of dimethyl sulphoxide and 448 mg (6.4 mmol, 5 eq) of sodium methanethiolate are added. The reaction mixture is heated for 16 h at 90° C. The reaction medium is diluted with 50 ml of ethyl acetate and then washed with 50 ml of a saturated ammonium chloride solution then 2×50 ml of distilled water. The organic phase is dried over magnesium sulphate then filtered and concentrated to dryness. The residue is purified by chromatography over 40 g of silica with, as eluent, heptane/ethyl acetate (7/3). The product obtained is put back into solution in ethyl acetate, heptane is added until the solution becomes cloudy, it is then cooled to 0° C. and filtered. 2-[(6-Methylsulphanylpyridin-2-ylamino)methyl]phenol is obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH:7]1[O:14][CH:6]21)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C@@H:7]([OH:14])[C@@H:6]2[N:15]=[N+:16]=[N-:17])#[N:2]
Reactant: CC1(C)c2ccc(C#N)cc2C2OC21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)c2ccc(C#N)cc2[C@@H](N=[N+]=[N-])[C@@H]1O
Temperature: 60 °C
Yield: 56.3 %

Procedure:
A mixture of 5-cyano-1,1-dimethyl-2,3-epoxyindane (1.34g), sodium azide (0.533g), and ammonium chloride (0.44g) in dry N,N-dimethylformamide (20 ml) was stirred and heated at 60° C., under nitrogen, for 3h. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and then dried (Na2SO4). Removal of solvents in vacuo, followed by chromatography of the residue (Si gel, eluted with 30% EtOAc in pentane) gave the title compound as a gum (0.93g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:16][CH2:15][C:12]1[NH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10](=[O:17])[CH:11]=1)(=[O:20])[CH3:19]
Reactant: O=c1cc(CO)[nH]cc1OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of 10 g of 5-(benzyloxy)-2-(hydroxymethyl)pyridin-4(1H)-one in 58 mL of pyridine, 4.6 mL of acetyl chloride was added under cooling with ice, and the mixture was stirred at 60 to 70° C. for 3 hours. The solvent was distilled off under reduced pressure, water was added thereto, and the mixture was stirred under cooling with ice. The solid was filtered off, chloroform was added thereto and the resultant was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Thereto was added diethyl ether and the solid was filtered off to obtain 9.2 g of (5-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)methyl acetate as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[CH2:20][CH2:19]2)=[N:6][CH:7]=1.CO.N.[SH2:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30](=[S:36])[NH2:31])[CH:25]=3)[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: S
Reactant: N#Cc1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=S)c1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Reaction time: 48 h
Yield: 70 %

Procedure:
A pressure tube was charged with N-(5-chloropyridin-2-yl)-2-[1-(2-cyanopyridin-4-yl)piperidin-4-ylmethylamino]benzamide (50 mg, 0.11 mmol) and 1:2 methanol:tetrahydrofuran (3 mL); and the solution was treated with ammonia(g), sealed, and allowed to stir for 2 days. The mixture was then treated with hydrogen sulfide (g), sealed and allowed to stir for 2 days. The mixture was concentrated and the residue purified by column chromatography (SiO2: 2% methanol in methylene chloride) affording 38 mg (70%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[ClH:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH:19][NH2:20])[CH:16]=[CH:17][CH:18]=1.C(O)(=O)C>C(O)C>[ClH:10].[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[N:20]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: COc1cccc(NN)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.0 g, 40 mmol) and 3-methoxy-phenylhydrazine hydrochloride (7.0 g, 40 mmol) in anhydrous ethanol (200 mL) was added acetic acid (1.2 mL). The reaction mixture was heated at reflux overnight, then cooled to room temperature and concentrated at reduced pressure. The residue was combined with ethyl acetate (200 mL), and washed with saturated aq NaHCO3, water, and brine. The solution was dried over Na2SO4, evaporated at reduced pressure and the solid residue was re-dissolved in ethanol (100 mL). A solution of 2M HCl in ether was added and the mixture was stirred for 30 min. The solvent was removed at reduced pressure, the solid residue was triturated and washed with hexane (50 mL) and then dried in a vacuum oven overnight to give the product 5-tert-butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride (5.46 g, 56%) as an off-white solid. 1H-NMR (DMSO-d6) δ 7.50 (t, 1H), 7.10 (m, 3H), 5.60 (s, 1H), 3.80 (s, 3H), 1.30 (s, 9H); MS LC-MS [M+H]+=246.2, RT=1.90 min.