Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[C:36]([O:40][CH2:41][CH2:42][CH2:43][CH2:44]O)(=[O:39])[CH:37]=[CH2:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:36]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][O:11][C:10]1[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:8][C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([OH:31])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])=[CH:6][C:5]=1[C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:39])[CH:37]=[CH2:38]
Reactant: C=CC(=O)OCCCCO
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCOc1c(C(C)(C)C)cc(SC(C)(C)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C(C)(C)C
Yield: 28.6 %

Procedure:
To a solution of probucol (2.58 g, 5 mmol) in THF (50 ML) were added 4-hydroxybutyl acrylate (1.0 ml, 10 mmol), triphenylphosphine (2.62 g, 10 mmol) and diethyl azodicarboxylate (1.57 ml, 10 mmol). The resultant mixture was stirred under nitrogen at reflux over weekend. It was evaporated. Silica gel chromatography (hexanes/dichloromethane 4:1) gave the title compound as a brown oil (0.92 g). 1H-NMR (400 MHz, CDCl3): 7.54 (s, 2 H), 7.46 (s, 2 H), 6.42 (dd, 1 H), 6.14 (dd, 1 H), 5.84 (dd, 1 H), 5.38 (s, 1 H), 4.23 (t, 2 H), 3.75 (t, 2 H), 1.97 m, 2 H), 1.82 (m, 2 H), 1.46 (s, 6 H), 1.45 (s, 18 H), 1.42 (s, 18 H).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]1)(=[O:26])[CH2:24][CH3:25].N12CCCN=C1CCCCC2>CN(C)C=O>[C:23]([N:27]1[CH2:28][CH2:29][CH:30]([C:33]([O:35][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:34])[CH2:31][CH2:32]1)(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 34.5 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 1-propionyl-4-piperidinecarboxylic acid (5.5 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g), and by recrystallization in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 1-propionyl-4-piperidinecarboxylate (4.9 g), m.p. 189° C., is obtained.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([O-:13])=[O:12].Cl>N1C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([NH:17][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:18]=[CH:19][CH:20]=1)([O-:13])=[O:12]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 100 °C
Yield: 80 %

Procedure:
Benzenesulfonyl chloride (6.01 mL, 46.8 mmol) was added to a solution of 3-nitroaniline (6.47 g, 46.8 mmol) in pyridine (50 mL) at room temperature. The mixture was heated to 100° C. for 1 h. Most of the pyridine was evaporated under reduced pressure. The resulting brown oil was dissolved in CH2Cl2 (100 mL) and washed with aqueous HCl (150 mL, 50 mmol). A tan solid precipitated out from the acidic aqueous phase. The solid was collected by filtration, washed with CH2Cl2 and dried under vacuum (10.41 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (1H, s), 7.93 (1H, s), 7.85-7.89 (1H, m), 7.79-7.83 (2H, m), 7.61-7.67 (1H, m), 7.49-7.61 (4H, m).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[CH:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32].[N+](=[CH:36][Si](C)(C)C)=[N-]>CO.C1(C)C=CC=CC=1>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[CH:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([O:29][CH3:36])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OC)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (1 g, 2.190 mmol) in MeOH (5 mL) and toluene (5.00 mL) was added (diazomethyl)trimethylsilane (1.642 mL, 3.28 mmol). The reaction mixture was stirred for 3 hours at room temperature. TLC indicated starting material was consumed and a new product was formed. The reaction mixture was concentrated under reduced pressure to give the desired product (1R,3aS,5aR,5bR,7aR,9S,11aR,13aR,13bR)-methyl 9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate as a white solid (1 g, 97%). 1H NMR (500 MHz, DMSO-D6) δ ppm 0.65 (s, 3H), 0.76 (s, 3H), 0.87 (d, J=12.67 Hz, 6H), 0.94 (s, 3H), 0.96-1.63 (m, 18H), 1.65 (s, 3H), 1.72-1.87 (m, 2H), 2.03-2.16 (m, 2H), 2.85-3.09 (m, 3H), 3.60 (s, 3H), 4.26 (d, J=4.58 Hz, 1H), 4.58 (s, 1H), 4.70 (d, J=1.83 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([Cl:9])[CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C)C(=O)C>[Cl:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: Fc1ccc(Cl)cc1Cl
Solvent: CC(=O)N(C)C
Product: Clc1ccc(N2CCNCC2)c(Cl)c1
Temperature: 165 °C
Yield: 76 %

Procedure:
A mixture of 1,3-dichloro-4-fluorobenzene (Aldrich; 4.21 g), piperazine (Aldrich; 11.0 g), and N,N-dimethylacetamide (Aldrich; 15 mL) is heated at 165° C. for 6.5 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated under reduced pressure to give 4.48 g of 1-(2,4-dichlorophenyl) piperazine. 1H NMR (CDCl3) δ3.00, 3.06, 6.96, 7.19, 7.36.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([OH:16])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([OH:16])[C:11]=1[I:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1cc(COCc2ccccc2)ncn1
Solvent: ClC(Cl)Cl
Product: Oc1ncnc(COCc2ccccc2)c1I

Procedure:
A solution of 6-benzyloxymethyl-4-hydroxy-pyrimidine (4.55 g, 20.87 mmol) and N-iodosuccinimide (5.165 g, 23 mmol) in chloroform (250 ml) was kept at reflux under argon for 2 h. The solution was washed with water, 0.5 N sodium thiosulfate, and brine. After drying (MgSO4), filtration and concentration gave a white solid (6.56 g. 91%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([C:27](OCC)=[O:28])([CH3:26])[CH3:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]([CH3:26])([CH3:25])[C:27](=[O:28])[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCNC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C(=O)N2CCCC2)CC1
Reaction time: 0.08 h

Procedure:
Amine preparation: to pyrrolidine (390 uL) in dry THF (4 mL) at 0° C. was added nBuLi (1.86 ml) The reaction mixture was stirred for 5 minutes and then 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (700 mg) in THF (5 mL) was added. The reaction mixture was stirred at room temperature for 24 h and then quenched with aqueous ammonium chloride, extracted into DCM, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (745 mg). Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:23]=[CH:22][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH:50]2[CH2:52][O:51]2)=[CH:44][CH:43]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH3:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:52][C@H:50]([OH:51])[CH2:49][O:48][C:45]3[CH:46]=[CH:47][C:42]([OH:41])=[CH:43][CH:44]=3)=[CH:23][CH:22]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: O=CO
Product: CNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 16.7 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-methyl-1-piperidinecarboxamide formate (0.322 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.364 g, 0.90 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.1 g, 0.15 mmol).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([CH:8]([CH2:11][CH2:12][CH3:13])[CH2:9]O)[CH2:6][CH3:7]>>[Br:2][CH2:9][CH:8]([CH2:11][CH2:12][CH3:13])[CH2:5][CH2:6][CH3:7]
Reactant: BrP(Br)Br
Reactant: CCCC(CO)CCC
Product: CCCC(CBr)CCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 168.4 %

Procedure:
Phosphorus tribromide (33.3 g, 0.123 mol) was added dropwise to 2-propyl-1-pentanol (40 g, 0.307 mol) at −10° C. to maintain the temperature below 0° C. and the mixture was stirred overnight at room temperature. The reaction mixture was heated at 100° C. for 1 h, cooled to room temperature, and poured into ice water (250 ml). The organic layer was separated, washed with conc. H2SO4 (25 ml) followed by saturated K2CO3 (25 ml), dried and distilled in vacuo (80° C./15 mm Hg) to furnish 40 g (83%) of 1-bromo-2-propylpentane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.C(OCC)(=O)C>[Si:23]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Methyl (2S,4R)-N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (22.1 g, 82.6 mmol) was dissolved in dry DMF (100 mL) under nitrogen. Imidazole (16.8 g, 248 mmol) was added and the mixture cooled to 0° C. tert-Butyldimethylsilyl chloride (13.1 g, 86.7 mmol) was added in small portions and then the mixture was allowed to warm to room temperature. After stirring overnight, the mixture was diluted with 300 mL ethyl acetate and washed with water three times (500 mL, 200 mL, 200 mL). The organic extracts were washed one final time with brine and then dried over MgSO4, filtered and concentrated to give 29.5 g (99%) of desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1(O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>C(O)C.[Pd]>[CH:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:15])[F:16])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: OC1(c2ccccc2C(F)(F)F)CCCC1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ccccc1C1CCCC1
Yield: 90.6 %

Procedure:
To a solution of 1-(2-(trifluoromethyl)phenyl)cyclopentanol (5.1 g, 22.15 mmol) in ethanol (32 mL) was added 10% Pd—C (500 mg; Degussa; wet) and the mixture was hydrogenated overnight with a hydrogen balloon. The reaction mixture was filtered through Celite®. The filtrate was poured into ice-water (100 mL) and extracted with CH2Cl2 (2×70 mL). The combined CH2Cl2 layer was washed with water (1×75 mL), dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound (4.3 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.58-1.67 (m, 4H), 1.81-1.90 (m, 2H), 2.06-2.15 (m, 2H), 3.32-3.43 (m, 1H), 7.22-7.26 (m, 1H), 7.45-7.51 (m, 2H), 7.58 (d, J=8 Hz, 1H).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:14][C:15]([O-:17])=[O:16].[K+]>CN(C=O)C.O>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:17][C:15](=[O:16])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1
Reactant: COC(=O)C(Br)c1cccc(Br)n1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)=O)c1cccc(Br)n1
Temperature: 120 °C

Procedure:
Methyl bromo(6-bromopyridin-2-yl)acetate (Example 360, Step 1) (500 mg, 1.62 mmol) and KOAc (635 mg, 6.47 mmol) were taken up in DMF (3.0 mL) and heated to 120° C. for 20 minutes in a microwave. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. Silica gel chromatography (0-40% EtOAc/hexanes) afforded the title compound as a pale yellow solid.
Reaction SMILES: [Na+].[CH3:2][C:3]([CH3:10])([CH3:9])[C:4](=O)[C:5]([O-:7])=[O:6].Cl.[NH2:12][OH:13]>O>[CH3:2][C:3]([CH3:10])([CH3:9])[C:4](=[N:12][OH:13])[C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)C(=O)C(=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=NO)C(=O)O
Yield: 81.2 %

Procedure:
163 g (1 mole) 93.5% trimethylpyruvic acid sodium salt and 69.5 g (1 mole) hydroxylamine hydrochloride were dissolved at 40° C. in 450 ml water. The product crystallized out during slow cooling under agitation. After 1.5 h agitation in an ice bath the crystals were filtered off, washed with 150 ml ice water, dried in a vacuum at 60° C., and then further dried in a vacuum desiccator over phosphorus pentaoxide to constant weight. 117.8 g trimethylpyruvic acid oxime (81% yield) in the form of colorless crystals were obtained.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH:12]([NH:15][NH2:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([CH:24]=O)=[C:22](Cl)[N:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:17][C:18]1[N:19]=[CH:20][N:21]=[C:22]2[N:15]([CH:12]3[CH2:13][CH2:14][CH:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:10][CH2:11]3)[N:16]=[CH:24][C:23]=12
Reactant: CC(C)c1noc(C2CCC(NN)CC2)n1
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)c1noc(C2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Temperature: 140 °C
Yield: 36 %

Procedure:
A mixture of [4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-hydrazine (Intermediate 12; 230 mg, 1.0 mmol), 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 182 mg, 1.0 mmol) and sodium carbonate (218 mg, 2.1 mmol) in acetonitrile was heated in the microwave at 140° C. for 10 min. Saturated aqueous sodium carbonate was added and the reaction mixture was filtered. The filtrate was extracted with ethyl acetate, and the combined organic layers were dried (sodium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 10% ethyl acetate/hexanes to give 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (125 mg, 35%) as a white solid. Mass spectrum M+=346.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][N:11]=1.[N+](C1C=CC([O:29][P:30]([CH3:33])([CH3:32])=O)=CC=1)([O-])=O.N12CCCN=C1CCCCC2>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][P:30]([CH3:33])([CH3:32])=[O:29])[CH:17]=2)[NH:12][N:11]=1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Reactant: CP(C)(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CP(C)(=O)Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
The dimethylphosphinic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester compound is prepared according to procedure F using 230 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol (intermediate B) in solution with 245 mg of dimethylphosphinic acid 4-nitrophenyl ester in 5 ml of dichloromethane (stabilized with amylene) to which 170 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in solution in 2 ml of dichloromethane are added. After stirring for 24 h at ambient temperature, the solvent is evaporated off and the crude is purified by preparative LC/MS. The crystals obtained after concentration of the fractions are washed with ethyl acetate and then with isopropyl ether. 129 mg of expected product are collected. Yield=43%.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:8]([NH:20][C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])=[N:9][C:10]([CH3:19])=[N:11][C:12]=1[O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16].[C:30](=[O:32])=[O:31]>C1COCC1>[CH2:15]([CH:14]([O:13][C:12]1[C:7]([C:30]([OH:32])=[O:31])=[C:8]([NH:20][C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])[N:9]=[C:10]([CH3:19])[N:11]=1)[CH2:17][CH3:18])[CH3:16]
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-BuLi in THF was added a solution of [5-bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine in THF at −78° C. After stirring for 10 minutes, CO2(g) was added at −78° C. and stirred at that temperature for 1 hour, then gradually warmed to room temperature. The resulting mixture was quenched with water and adjusted to pH 2 to 3 and extracted with chloroform. The organic layer was separated, dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound as a solid, mp. 118-120° C., Anal. For C20H27N3O3 calc.: C, 67.20; H, 7.61; N, 11.76; found: C, 67.25; H, 7.87; N, 11.48.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:26])=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1)[N:5]=2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:27]1([C:30]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[CH:14][C:15]([F:26])=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=2)[N:5]=3)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)ccc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of tert-butyl {5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}carbamate (1.13 g, 3.0 mmol) and N,N-dimethylpyridin-4-amine (1.22 g, 10 mmol) in pyridine (10 mL) was added dropwise cyclopropanecarbonyl chloride (1.05 g, 10 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (0.78 g, 59%) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1.[BH3-]C#N.[Na+].CC(O)=O>CO>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][NH:11][C:10]2[CH:9]=[CH:8][NH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:13]1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1[nH]ccc1NCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.075 g, 0.49 mmol), indole-3-carboxaldehyde (0.085 g, 0.58 mmol), NaCNBH3 (0.031 g, 0.49 mmol) and HOAc (0.056 mL, 0.97 mmol) in methanol (3 mL) was stirred at r.t. overnight. The mixture was concentrated in vacuo and the crude product-mixture was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([S:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1.[Cl:18][C:19]1[N:23]([CH3:24])[N:22]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH3:32])[CH:26]=2)[C:20]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][S:9][C:8]1[C:3]([CH2:2][O:31][C:28]2[CH:29]=[CH:30][C:25]([C:21]3[C:20]([CH3:33])=[C:19]([Cl:18])[N:23]([CH3:24])[N:22]=3)=[CH:26][C:27]=2[CH3:32])=[C:4]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2nn(C)c(Cl)c2C)ccc1O
Reactant: CSc1cccc(-n2nnn(C)c2=O)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1cccc(-n2nnn(C)c2=O)c1COc1ccc(-c2nn(C)c(Cl)c2C)cc1C

Procedure:
A mixture of 1-(2-bromomethyl-3-methylthiophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Preparation example 13) 1.5 g, 4-(5-chloro-1,4-dimethyl-1H-pyrazol-3-yl)-2-methyl-phenol 1 g, potassium carbonate 0.9 g and acetonitrile 20 ml was stirred with heating under reflux for five hours. The reaction mixture was concentrated and the resulting residue was subjected to a silica gel column chromatography to give 1-{3-methylthio-2-[2-methyl-4-(5-chloro-1,4-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 38”) 2.1 g.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([O:53][CH3:54])=[C:47]([S:49](Cl)(=[O:51])=[O:50])[CH:48]=1>C(#N)C>[CH3:54][O:53][C:46]1[CH:45]=[CH:44][C:43]([Cl:42])=[CH:48][C:47]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 42.7 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0279 g, 0.0604 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-chloro-2-methoxybenzenesulfonyl chloride (0.0470 g, 0.195 mmol) to obtain 4-(2-methoxy-5-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0172 g, yield 434).