Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:23])[C:3]([OH:24])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Reaction time: 0.08 h
Yield: 56.8 %

Procedure:
A solution of 4-[(2-naphthalenyl)methoxy]-alpha-oxobenzeneacetic acid methyl ester (0.58 g) in methanol (3 mL) and tetrahydrofuran (8 mL) was treated with 1N sodium hydroxide (2.0 mL) and a white precipitate formed immediately. After 5 minutes, the reaction mixture was concentrated, the residue was acidified with excess hydrochloric acid and partitioned between dichloromethane (100 mL) and water (10 mL). The organic layer was dried (MgSO4) and concentrated. The resulting residue was crystallized from dichloromethane-hexane-tetrahydrofuran to give 0.315 g of 4-[(2-naphthalenyl)methoxy]-alpha-oxobenzeneacetic acid, mp 145°-146° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].C([O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=O)C>CCOCC.O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]2[CH2:20][CH:15]([CH2:13][OH:12])[CH2:16][CH2:17][N:18]2[C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(F)cc2)C1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
1-Bromo4-fluorobenzene (154 ml; 1.402 mol) in anhydrous ether (640 ml) was added to a suspension of magnesium turnings (34.1 g; 1.404 mol) in anhydrous ether (250 ml) and the mixture was stirred under nitrogen, at a rate which gave a gentle reflux. The solution was cooled, stirred at room temperature for 45 min and then cooled in an ice bath. To this solution was added dropwise over 40 min. a solution of 1-(triphenylmethyl)-4-piperidinecarboxylic acid ethylester (90 g; 0.225 mol) in anhydrous tetrahydrofuran (1.2 l). After 1 h the cooling bath was removed and the reaction was allowed to stand at room temperature overnight. The reaction mixture was then heated under reflux for 30 min, poured into ice-water and the product was extracted into ethyl acetate. The extract was filtered to remove insolubles, washed with water, dried over sodium sulfate and evaporated to yield an oil which on trituration with hot n-hexane gave the product as crystals (68.0 g); m.p. 243° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: OB(O)c1ccncc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: c1ccc2c(-c3ccncc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-pyridinylboronic acid to give ((1H-pyrazol-3-yl)-(1-pyridin-4-yl-isoquinolin-3-yl)-amine. LC-MS m/e 288(MH+).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH:11]([CH3:12])[C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31]([N:9]2[C:10](=[O:13])[CH:11]([CH3:12])[N:8]2[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:32])(=[O:28])=[O:29])=[CH:25][CH:26]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC1C(=O)NN1C(c1ccccc1)c1ccccc1
Product: CC1C(=O)N(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)N1C(c1ccccc1)c1ccccc1
Yield: 88 %

Procedure:
Following the procedure of Example 2 and using 1-(diphenylmethyl)-4-methyl-1,2-diazetidin-3-one (prepared according to Example 1B.) and p-chlorophenylsulfonylisocyanate there is obtained 1.7 g (88%) of the title compound having a melting point of 124°-129° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:22])=[CH:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F-].[K+]>O1CCCC1.O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:22])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)cnc1C1=CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(N)cnc1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1

Procedure:
To a solution of 6-(4-{[tert-butyl(dimethyl)silyl]oxy}-cyclohex-1-en-1-yl)-5-methylpyridin-3-amine (1.5 g) described in Reference Example 110, palladium acetate (211 mg) and potassium fluoride (1.09 g) in tetrahydrofuran (24 ml) and water (10 ml) was slowly added dropwise polymethylhydrosiloxane (PMHS) (1.12 ml) at room temperature with stirring, and then stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, filtered through Celite, and then the filtrate was concentrated to half of the volume. Then, saturated brine was added thereto, the mixture was extracted with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (1.35 g) as a light brown solid. MS (ESI) m/z: 321 (M+H)+.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH2:13]([O:15][C:16]([O:18][NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])=[O:17])[CH3:14].O>CN(C)C=O.C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH2:22]([O:21][C:20]([N:19]([CH2:2]/[CH:3]=[CH:4]/[P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[O:18][C:16]([O:15][CH2:13][CH3:14])=[O:17])=[O:24])[CH3:23]
Reactant: CCOC(=O)NOC(=O)OCC
Reactant: CCOP(=O)(/C=C/CBr)OCC
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)ON(C/C=C/P(=O)(OCC)OCC)C(=O)OCC
Yield: 42.1 %

Procedure:
A solution of diethyl 3-bromo-trans-1-propenylphosphonate (23.83 g.) in N,N-dimethylformamide (50 ml.) was added dropwise to a suspension of ethyl N-ethoxycarbonyloxycarbamate (19.94 g.) in N,N-dimethylformamide (100 ml.) at -25°~-30° C. in the course of 20 minutes. The reaction mixture was stirred at -20°--30° C. for an hour and at -5°~-10° C. for an hour. Subsequently, the resultant mixture was poured into a mixture of water (1 liter) and ethyl acetate (0.7 l). The ethyl acetate layer was separated and the aqueous layer was extracted twice with ethyl acetate (300 ml.). The combined ethyl acetate layer was washed with water (300 ml.), dried over magnesium sulfate and concentrated under reduced pressure to give an oily residue (28.89 g.), which was subjected to a column chromatography on silica gel [Developing solvent: a mixture of chloroform and ethyl acetate (4:1)]. The eluate was concentrated under reduced pressure to give oily diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-trans-1-propenylphosphonate (13.80 g.).
Reaction SMILES: COC1C=CC(B2OC(C)(C)C(C)(C)O2)=C[C:4]=1[CH2:18][S:19](N)(=[O:21])=[O:20].[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:46][CH:47]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.C(S(Cl)(=O)=O)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:18]([S:19]([N:51]1[CH2:52][CH2:53][N:48]([C:45]2[N:44]=[CH:43][C:42]([C:39]3[CH:40]=[C:41]4[C:33]([C:31]5[CH:30]=[N:29][N:28]([CH2:27][C:26]6[CH:64]=[CH:65][CH:66]=[C:24]([F:23])[CH:25]=6)[CH:32]=5)=[CH:34][N:35]([S:54]([C:57]5[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=5)(=[O:56])=[O:55])[C:36]4=[N:37][CH:38]=3)=[CH:47][CH:46]=2)[CH2:49][CH2:50]1)(=[O:21])=[O:20])[CH3:4]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CCS(=O)(=O)Cl
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(Cc5cccc(F)c5)c3)cn4S(=O)(=O)c3ccc(C)cc3)cn2)CC1
Yield: 100 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (80 mg, 0.13 mmol) was alkylated with ethanesulfonyl chloride (25 mg, 0.196 mmol) using triethylamine (40 mg, 0.39 mmol) in DCM (3 mL) to afford 100 mg (100% yield) of the titled compound. MS: m/z=700.2 (M+1).
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].CS(O[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=1)(=O)=O>CN(C=O)C.CCOC(C)=O>[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[CH:21]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: Cc1cccc(COS(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(COc2cccc([C@H](O)CCNC(=O)OC(C)(C)C)c2)n1
Temperature: 90 °C

Procedure:
Phenol (7, Intermediate I) (0.50 g, 1.87 mmol) and K2CO3 (1.29 g, 9.35 mmol) were added to a solution of (6-methylpyridin-2-yl)methyl methanesulfonate (412 mg, 2.05 mmol) in DMF (20 mL) and the reaction mixture was heated under reflux at 90° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with water and brine. Drying over anhydrous Na2SO4 and concentration under reduced pressure gave (R)-tert-butyl (3-hydroxy-3-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propyl)carbamate as pale yellow liquid. Yield (200 mg, 72%); 1H NMR (400 MHz, CDCl3); δ 7.59 (t, J=8.0 Hz, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.87 (dd, J=8.0, 2.4 Hz, 1H), 5.17 (s, 2H), 4.86 (bs, 1H), 4.71 (bs, 1H), 3.49-3.48 (m, 1H), 3.19-3.11 (m, 2H), 2.57 (s, 3H), 1.88-1.82 (m, 2H), 1.45 (s, 9H); MS: m/z 373.20 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](C1C=CC(B(O)O)=CC=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1

Procedure:
In a like manner as described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-tert-butylphenylboronic acid (302 mg, 1.70 mmol) were coupled to yield 2-(4-tert-butyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 150 mg (42%), as a white solid. mp 243-244° C.; 1H NMR (300 MHz, d6-DMSO) δ 1.33 (s, 9H), 3.05 (m, 2H), 3.38 (m, 2H), 7.20 (app t, 1H, J=7.8 Hz), 7.57 (m, 5H), 7.67 (dd, 1H, J=7.2, 0.6 Hz), 8.07 (br t, 1H), 11.51 (br s, 1H); HRMS (FAB, MH+) Calcd for C21H23N2O: 319.1810, Found: 319.1813; Anal. (C21H22N2O.0.3 H2O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>C(O)CCC>[NH2:1][C:2]1[C:7]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[N:6][CH:5]=[N:4][C:3]=1[Cl:9]
Reactant: N#Cc1ccc(N)cc1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCCCO
Product: N#Cc1ccc(Nc2ncnc(Cl)c2N)cc1
Yield: 60.2 %

Procedure:
A solution of 5-amino-4,6-dichloropyrimidine (7.00 g, 42.7 mmol) and 4-aminobenzonitrile (5.04 g, 42.7 mmol) in n-butanol (130 ml) was heated at reflux for 16 hours. After cooling the mixture the solid which precipitated out was filtered off, and partitioned between dichloromethane (500 ml) and saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give the title compound (6.31 g, 60%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15](O)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(C(=O)N4CCN(C)CC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 1-Methyl-piperazine to give [1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-(4-methyl-piperazin-1-yl)-methanone. LC-MS: m/e 409 (MH+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH:26]=O)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O-:30])=[O:29].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH2:26][N:40]3[CH2:41][CH2:42][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N+:28]([O-:30])=[O:29])[CH2:38][CH2:39]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3ccccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
To a stirred solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (0.060 g, 0.15 mmol) and 1-(2-nitro-phenyl)-piperazine (0.032 g, 0.157 mmol) in CH2Cl2 (0.5 mL), glacial AcOH (8.5 μL, 0.15 mmol) was added and stirred for 15 min at room temperature. NaBH(OAc)3 (0.041 g, 0.19 mmol) was added and stirred under nitrogen overnight. Saturated NaHCO3 (0.5 mL) was then added and stirred for 15 min. The layers separated and the aqueous layer was extracted with CH2Cl2 (0.5 mL). MPLC purification (silica, 2-15% MeOH/CH2Cl2) afforded the desired product as a white solid (0.063 g, 71%). TLC (silica, 12% MeOH/CH2Cl2): Rf=0.67. MS (electrospray): exact mass calculated for C27H31F3N6O4S, 592.21; m/z found, 593.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.80 (dd, J=1.6, 8.2 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.52 (ddd, J=1.6, 7.3, 8.3 Hz, 1H), 7.19 (dd, J=1.2, 8.3 Hz, 1H), 7.09 (m, 1H), 4.59 (s, 2H), 4.17 (t, J=6.9 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 3.13 (br t, J=4.8 Hz, 4H), 2.96 (t, J=5.6 Hz, 2H), 2.95 (s, 3H), 2.66 (br t, J=4.4 Hz, 4H), 2.51 (t, J=7.0 Hz, 2H), 2.17 (q, J=6.9 Hz, 2H).
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH2:16]O)[CH:11]=[CH:12][CH:13]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:16][CH:15]=[CH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:19])([F:18])[F:6])[CH:9]=1
Reactant: OCC=Cc1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(C=CCCl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
Dimethylformamide (5 mL) was added to a solution of 3-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol (50 g) in dichloromethane (500 mL) at 0 to 5° C. Thionyl chloride (44.2 g) was slowly added to the above mixture maintaining the temperature at about 0 to 5° C. The reaction mixture was stirred at 0 to 5° C. for 1-2 hours. After completion of the reaction, the mixture was quenched with ice-chilled de-ionized water (250 mL) at 0-10° C. and stirred for 30 minutes. Organic layer was separated, washed twice with a solution of sodium chloride (10%; 250 mL) and concentrated under vacuum to give 1-[3-chloroprop-1-en-1-yl]-3-(trifluoromethyl)benzene.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:32]([NH2:35])[CH2:33][CH3:34].[BH4-].[Na+]>ClCCl.CO.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:35][CH2:32][CH2:33][CH3:34])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCCN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.046 mmol) in dichloromethane (0.7 mL) and methanol (0.7 mL) was added propylamine (22 uL, 0.27 mmol) and 1 drop of acetic acid. This mixture was stirred for 1 h at room temperature and then sodium borohydride (10 mg, 0.27 mmol) was added. The reaction was stirred overnight at ambient temperature, and the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (22.1 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([Cl:16])[C:12]([CH3:17])=[N:11]1.[CH2:18](Br)[C:19]#[CH:20].C[O-].[Na+].[Na]>C1(C)C=CC=CC=1.O.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:20][C:19]#[CH:18])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([Cl:16])[C:12]([CH3:17])=[N:11]1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(C)c1Cl
Reactant: C#CCBr
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCOc1cc(-n2nc(C)c(Cl)c2C)c(Cl)cc1Cl
Reaction time: 3 h
Yield: 91.2 %

Procedure:
1-(2,4-dichloro-5-hydroxyphenyl)-3,5-dimethyl-4-chloropyrazole (29.2 g) and propargyl bromide (12.0 g) were added to a solution of sodium methoxide which was previously prepared from metallic sodium (2.3 g) and methanol (200 ml). The resulting mixture was heated under reflux, with stirring for 3 hours. To the reaction mixture, after cooling, were added water and toluene to form two layers. The toluene layer as formed was separated, washed with water and then dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (30.1 g) as a pale brown crystalline solid. Recrystallization of this solid from a mixture of cyclohexane/acetone afforded a white crystalline solid. m.p. 156.5°-158° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[CH:6]([NH2:21])[C:7](=[O:20])[CH2:8][CH2:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)[CH3:3].[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>CN(C=O)C.C1COCC1>[CH2:2]([O:4][C:5](=[O:22])[CH:6]([NH:21][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[CH3:23])[C:7](=[O:20])[CH2:8][CH2:9][C:10]12[CH2:17][CH:16]3[CH2:18][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH2:19]1)[CH2:11]2)[CH3:3]
Reactant: CCOC(=O)C(N)C(=O)CCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)c1ccccc1C)C(=O)CCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
5-Adamantan-1-yl-2-amino-3-oxo-pentanoic acid ethyl ester hydrochloride (prepared using the method of T. W. von Geldem & C. Hutchins et al, J. Med. Chem. 1996, 39, 957) (3.30 g, 10.0 mmol) was suspended in DMF (15 ml) and a solution of 2-methylbenzoyl chloride (1.55 g 10.0 mmol) in THF (15 ml) was added. The mixture was stirred at room temperature and a solution of N,N-diispropylethylamine (3.48 ml 20.0 mmol) in THF (10 ml) was added dropwise over 30 min. After stirring for 2 h the THF was evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, washed with water, 2M HCl, brine, dried (MgSO4), and the solvent was evaporated. The residue was purified by flash column chromatography (silica, DCM/hexane/ethyl acetate 9:9:2) to afford the product as a pale yellow oil. (2.08 g, 60%). 1NMR (300 MHz, CDCl3) 7.49-7.23 (4H, m), 6.97 (1H, d), 5.45 (1H, d), 4.30 (2H, m), 2.77 (2H, m), 2.47 (3H, s), 1.97 (3H, s) 1.67 (6H, m), 1.47 (8H, m), 1.34 (3H, t).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].[Cl-].[NH4+]>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccccc2OC)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 98.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.18 g of 2-methoxyphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.3 g of 4-(2-methoxyphenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (32)).