Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=C(C=C(OCC2C=CC=CC=2)C=1)CN)C1C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=1[OH:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][C:34]=1[OH:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: NCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: NCc1ccc(OCc2ccccc2)c(O)c1
Yield: 33 %

Procedure:
This compound was prepared according to procedure used in preparation of 3,5-dibenzyloxybenzylamine, starting from 4-benzyloxy-3-hydroxybenzonitrile. Yield was 33%. MP 122-125° C.; 1H NMR (DMSO-d6, 400 MHz) δ 8.9 (br, 1H), 7.44 (d, 2H, J=7.4 Hz), 7.35 (dd, 2H, J=7.0 and 7.7 Hz), 7.28 (dd, 1H, J=7.0 and 7.3), 6.85 (d, 1H, J=7.6 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.61 (dd, 1H, J=7.4 and 2.2 Hz), 5.05 (s, 2H), 3.55 (s, 1H), 2.50 (br, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:18])=[CH:7][CH:8]=2)[O:3]1.[H-].[Na+].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:11][CH:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:18][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])=[CH:7][CH:8]=2)[O:3]1
Reactant: CN(C)CCCl
Reactant: CC1(C)CC(c2ccccc2)c2ccc(O)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1ccccc1

Procedure:
A mixture of 2,2-dimethyl-7-hydroxy-4-phenylchroman (3.72 g), sodium hydride (0.53 g, 60% dispersion in oil) and 2-dimethylaminoethyl chloride (1.58 g) in toluene (59 ml) was stirred and boiled under reflux for 6 hours. Water was added to the cooled mixture and the organic layer was separated and extracted with 5 N hydrochloric acid (3×30 ml). The combined acid extract was basified, extracted with ether and the ether extract dried (magnesium sulphate). Removal of the solvent gave 2,2-dimethyl-7-dimethylaminoethoxy-4-phenylchroman which was isolated as its hydrochloride salt, m.p. 165°-167° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.Cl.[O:24]1[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[CH:6]=[N:5][C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=2[C:2]=1[NH:30][CH:26]1[CH2:27][CH2:28][CH2:29][O:24][CH2:25]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCCOC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCOC1
Temperature: 82 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
A stirred suspension of 4-chloro-5-nitro-1-(phenyl sulfonyl)-1H-pyrrolo[2,3-b]pyridine (11.10 g, 33.0 mmol) in isopropanol (IPA) (100 ml) was treated with tetrahydro-2H-pyran-3-amine hydrochloride (5.0 g, 36.0 mmol) and N,N-diisopropylethylamine (15.0 mL, 84.0 mmol), and stirred at 82° C. for four hours. The mixture was then cooled and left to stand at 5° C. for 2 h. The resulting precipitate was collected by filtration and washed with IPA. Trituration (water) afforded 11.7 g (89%) of 5-nitro-1-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine. LCMS (Method E, ESI): RT=1.65 min, m+H=403.2; 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J=7.6 Hz, 1H), 9.11 (s, 1H), 8.20 (d, J=8.0 Hz, 2H), 7.69-7.56 (m, 2H), 7.60-7.42 (m, 2H), 6.76 (d, J=4.2 Hz, 1H), 4.14 (ddt, J=10.7, 7.1, 3.5 Hz, 1H), 3.98 (dd, J=11.5, 2.7 Hz, 1H), 3.85-3.62 (m, 2H), 3.58 (dd, J=11.5, 6.4 Hz, 1H), 2.27-2.06 (m, 1H), 1.86 (tdt, J=11.8, 7.5, 3.9 Hz, 2H), 1.79-1.63 (m, 1H).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][S:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][S:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CSc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 90 %

Procedure:
Prepared analogously to Example 27 from 1-methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 90% of theory, C28H29N5O3S (515.64) Rf value:0.24 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) ##EQU11##
Reaction SMILES: [C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5].[N+:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)(=O)C>[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([O:25][C:1](=[O:26])[CH2:2][CH2:3][C@H:4]([C@@H:6]2[C@:23]3([CH3:24])[C@H:9]([C@H:10]4[C@H:20]([CH2:21][CH2:22]3)[C@:18]3([CH3:19])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]4)[CH2:8][CH2:7]2)[CH3:5])=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](CCC(=O)Oc1ccc([N+](=O)[O-])cc1)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C

Procedure:
Cholanic acid (3.6 g, 10.0 mmoles) is suspended in methylene chloride (200 mL) and stirred well at ambient temperature. 4-Nitrophenol (1.4 g, 10.1 mmoles) and N,N′-dicylcohexylcarbodiimide (2.1 g, 10.2 mmoles) are added, and the mixture is stirred overnight. The mixture is then filtered, the solid washed with a little methylene chloride, and the filtrate is evaporated to dryness to give a yellow solid. The crude product is dissolved in ethyl acetate (100 mL). The solution is filtered and the filtrate si evaporated to give an off-white solid. The solid is crystallized from hot hexanes. The yield is 3.9 g (80%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([CH:20]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:28][CH:27]=2)[CH2:21][CH2:22][CH3:23])[CH3:19]>>[CH3:17][CH:18]([CH:20]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:28][CH:27]=2)[CH2:21][CH2:22][CH3:23])[CH3:19]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCC(c1cc2cc(/C(C)=C/C(=O)O)ccc2[nH]1)C(C)C
Product: CCCC(c1cc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc2[nH]1)C(C)C

Procedure:
0.93 g of compound 21 was obtained in a similar manner to those described in the Examples 1 and 2 using 2.20 g of ethyl 4-(2-aminophenoxy)butyrate and 1.50 g of 3-[1-(1-methylethyl)butylindol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[CH2:42]([CH2:44][NH2:45])[OH:43]>C(Cl)Cl>[OH:43][CH2:42][CH2:44][NH:45][C:30]([C:29]1[CH:33]=[CH:34][C:26]([C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:13]3[C:12]([NH:11][CH:8]([CH3:9])[CH3:10])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:19][CH2:20]2)=[O:25])=[N:27][CH:28]=1)=[O:31]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: NCCO
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCO)cn2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Triethylamine (0.54 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazine-4-yl-carbonyl]nicotinic acid (1.3 g) in methylene chloride (40 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0.45 ml) at 0° C.˜5° C., the reaction mixture was stirred at 5° C. for 2 hours. With the addition of triethylamine (0.6 ml) and ethanolamine (0.25 ml), the mixture was stirred at 5° C.˜10° C. for 3 hours. The solution was washed with aqueous sodium bicarbonate and water twice. The separated organic layer was concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization and recrystallized with ethanol and isopropyl ether to give a desired compound of 1.2 g (yield: 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:34][C@@H:35]1[CH:40]2[CH2:41][CH2:42][N:37]([CH2:38][CH2:39]2)[CH2:36]1.CO>C(Cl)Cl>[N:37]12[CH2:42][CH2:41][CH:40]([CH2:39][CH2:38]1)[C@@H:35]([NH:34][C:14]([C:12]1[S:13][C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:10][CH:11]=1)=[O:16])[CH2:36]2
Reactant: O=C(O)c1ccc(Sc2ccc(Cl)cc2)s1
Reactant: N[C@H]1CN2CCC1CC2
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Sc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
TEA (1.5 mL, 10.9 mmol) was added to a suspension of the product of Step 33b (2.7 g, 10 mmol) in CH2Cl2 (100 mL). Diphenylchlorophosphate (2.08 mL, 10 mmol) was added and the resulting solution is stirred at room temperature for 30 minutes. To this solution is added a solution of (R)-3-aminoquinuclidine (1M in DMF, 9.1 mL, 9.1 mmol). The resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH, then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness and the resulting solid is triturated with ether and dried in vacuo to yield the desired product (2.4 g, 71%). Alternatively, these compounds can be converted to their hydrochloride salts and crystallized from MeOH/IPA. MS for C18H19ClN2OS2 (ESI) (M+H)+ m/z 379.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([O:8]/[CH:9]=[C:10]2\[CH:11]3[CH2:25][CH:24]=[CH:23][CH:12]3[N:13](C(OC(C)(C)C)=O)[C:14]\2=[O:15])[CH:3]=1.[Cl-].[Mg+2].[Cl-].C(Cl)Cl>C(#N)C>[CH3:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([O:8]/[CH:9]=[C:10]2\[CH:11]3[CH2:25][CH:24]=[CH:23][CH:12]3[NH:13][C:14]\2=[O:15])[CH:3]=1
Reactant: CC1=CC(O/C=C2/C(=O)N(C(=O)OC(C)(C)C)C3C=CCC23)OC1=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: ClCCl
Product: CC1=CC(O/C=C2/C(=O)NC3C=CCC23)OC1=O
Yield: 40 %

Procedure:
A solution of tert-butyl (3E)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]-2-oxo-4,6a-dihydro-3aH-cyclopenta[b]pyrrole-1-carboxylate Ib-1 (28 mg, 0.080 mmol) in acetonitrile (1 mL) was stirred with magnesium chloride (23 mg, 0.24 mmol) at 40° C. for 7 h. The solution was then diluted into CH2Cl2, filtrated, concentrated and purified by flash chromatography (EtOAc, then 5% MeOH in CH2Cl2) giving the desired compound as a colorless oil (8 mg, 40%); 1H NMR (400 MHz, CDCl3) 7.27 (1H, s), 6.93 (1H, s), 6.54 (1H, brs), 6.14 (1H, s), 5.87 (1H, d), 5.71 (1H, brs), 4.65 (1H, d), 3.66 (1H, m), 2.83 (1H, m), 2.46 (1H, d), 2.02 (3H, s): LCMS (Method A): 0.63 min; ES+270 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([NH:26][CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:28](O)=[O:29])=[O:25])=[CH:18]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:28](=[O:29])[CH:27]([NH:26][C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:14])=[CH:23][CH:22]=3)=[O:25])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
1-Piperazinecarboxylic acid t-butyl ester (1.2 mmol) and 2-[(5chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.6 mmol) were coupled according to procedure A (0-25° C. reaction temperature, reaction time 4 days, extraction with acid first, then base), and the crude product purified by column chromatography on silica gel eluted with 30% ethyl acetate in hexanes to give a colorless foam: Yield 290 mg, 95%; HPLC (70/30) 6.23 min (99%); PBMS 512/514 (MH+, 100%);
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21](C(=O)C(F)(F)F)=[CH:20][CH:19]=2)[N:7]=1)=[O:4].[C:32](OC(=O)CC)(=O)CC>CN(C)C1C=CN=CC=1.O>[C:18]1([N:8]2[CH:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[CH2:10][C:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:32])=[N:7]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: Cc1ccc(C2CC(NC(=O)C(F)(F)F)=NN2c2ccc(C(=O)C(F)(F)F)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Product: CCC(=O)NC1=NN(c2ccccc2)C(c2ccc(C)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of 4.5 g. of 3-amino-1-phenyl-5-p-tolyl-2-pyrazoline (prepared in Example 3), 20.0 ml. of propionic anhydride and 200 mg. of 4-dimethylaminopyridine is heated on a steam bath for 2 hours. The reaction mixture is cooled to room temperature then water is added to separate a solid. The solid is collected then is dissolved in dichloromethane. The solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated at reflux and hexane is added until turbidity appears. The mixture is cooled and filtered to collect a solid. The solid is recrystallized again from 80% ethanol. This material is dissolved in 100 ml. of methanol, then 200 mg. of potassium carbonate is added and the mixture is refluxed for 15 minutes. Water is added until turbidity appears. The mixture is cooled and filtered to collect the solid. The solid is dissolved in dichloromethane. This solution is columnized and recrystallized as described above to yield 2.4 g. of the desired product as colorless needles, m.p. 123.5° -125° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][N:8]=[C:9]([NH2:11])[CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>C(OCC)(=O)C>[NH2:11][C:9]1[N:8]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:21])[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:10]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccco2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-Furan-2-yl-2H-pyrazol-5-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using 100% ethyl acetate afforded the title compound as a white solid. 1H NMR (400 MHz, CD6CO); 7.48-7.52 (m, 1H), 6.98-7.06 (m, 2H), 6.52-6.56 (m, 2H), 6.44-6.48 (m, 2H), 5.74 (s, 1H), 4.98 (s, 2H), 3.68-3.88 (m, 4H), 3.12-3.24 (m, 4H). MS (ES) M+H) expected=369.4, found 370.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C>CC(O)C>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NCC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.8 mmol) in 2-propanol (40 mL) was added tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (420 mg, 2.0 mmol) followed by triethylamine (200 mg, 2.0 mmol). The reaction mixture was stirred at reflux for 15 hours. The solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-{[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester. (Yield 700 mg, 85.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[O:27]([CH2:26][CH2:25][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCOc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2ccccc2)cc1
Temperature: 110 °C

Procedure:
A mixture of 33 g of ethyl p-aminobenzoate, 80 ml of hexamethylphosphoramide and 20.1 g of β-bromophenetole is heated at 110° C. for 20 hours. The mixture is cooled, diluted with 25 ml of water, chilled, filtered and the solid washed with ethanol and with water to give crystals, mp 126°-129° C. Recrystallization from ethanol gives pale yellow crystals, mp 129°-131° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[SH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([S:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc(S)cc1
Reactant: COc1ccc(C(=O)O)cc1C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Crude 3-(tert.butyl)-4-methoxybenzoic acid, prepared starting with 1.04 g (5 mmoles) of 3-(tert.butyl)-4-methoxybenzoic acid, described in Example 35 of French Patent No. 85 13747 (2.570.377), is dissolved in 15 ml of dichloromethane. The solution is slowly added to a mixture of 771 mg (5 mmoles) of 4-mercaptobenzoic acid and 8 ml of pyridine. The reaction mixture is stirred at ambient temperature for 8 hours, evaporated to dryness, taken up in water, acidified to pH 5 with 1N HCl and extracted with ethyl ether. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting residue is purified by chromatography on a silica column (eluant: ethyl ether). The solvent is evaporated and 530 mg (32% yield) of 4-[3-tert.butyl-4-methoxybenzoylthio]benzoic acid whose melting point is 220°-221° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11](O)=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1COCC1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(CO)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
Under a nitrogen stream, to a solution of 2-bromo-terephthalic acid (5.0 g, 20.4 mmol) in THF (50 ml), a THF solution of BH3 (1.09 M, 74.9 ml) was added dropwise at 0° C. and the mixture was stirred at room temperature for 4 hours. After addition of THF-water (1:1) to this solution, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:2)) to give the titled compound (4.1 g, 92%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>CO>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([C:1](=[O:3])[CH3:2])=[CH:5][NH:6]2)=[CH:11][CH:10]=1
Reactant: CC(=O)c1c[nH]c2cc(CC(=O)O)ccc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)Cc1ccc2c(C(C)=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (3-acetyl-1H-indol-6-yl)-acetic acid [39689-58-2] (500 mg, 2.85 mmol) in MeOH (14 mL), cooled to at 0° C., was added (trimethylsilyl)diazomethane (2M solution in Et2O; 6.00 mL, 12.0 mmol). After stirring at RT for 30 min, the reaction mixture was concentrated in vacuo to afford the title compound as a yellow wax. MS: 190 [M+H]+; tR (HPLC conditions k): 3.20 min. The material thus obtained was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH2:19].N1C=CC=CC=1.S(=[N:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Br:38])[C:32](Cl)=[O:33])=O>O1CCCC1>[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Br:38])[C:32]([NH:19][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:5][C:4]=1[CH3:18])=[O:33]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: O=S=Nc1cc(C(=O)Cl)ccc1Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(Br)c(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a solution of 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (0.31 g, 1.1 mmol) (prepared according to EP 1,006,102) in anhydrous tetrahydrofuran (2 ml), at 20° C., was added sequentially pyridine (0.174 g, 2.2 mmol) and a solution of 3-sulfinylamino-benzoyl chloride (0.25 g, 0.86 mmol) (Example 1.2) in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred at ambient temperature for three hours. The reaction mixture was quenched by addition of water (5 ml). After separation of the phases, the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3) to give 3-amino-4-bromo-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.235 g, 78% yield). 1H-NMR (DMSO-d6, 400 MHz): 7.53 (d, 1H), 7.44 (s, 2H), 7.38 (d, 1H), 7.10 (q, 1H), 5.6 (s, 2H), 2.24 (s, 6H) ppm.