Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[N:13][C:12]=12)=[O:7])C.Cl>C(O)C>[C:17]([C:15]1[CH:14]=[N:13][C:12]2[N:11]([N:10]=[CH:9][C:8]=2[C:6]([OH:5])=[O:7])[CH:16]=1)(=[O:1])[NH2:18]
Reactant: CCOC(=O)c1cnn2cc(C#N)cnc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cnc2c(C(=O)O)cnn2c1
Temperature: 60 °C
Yield: 75 %

Procedure:
An aqueous solution of sodium hydroxide (10%, 5 mL) was added to a suspension of 6-cyano-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (0.35 mg, 1.62 mmol) in ethanol (5 mL) and the reaction mixture was heated at 60° C. for 5 hours. Ice-water was added and the resulting mixture was acidified until pH<1 by addition of an aqueous solution of hydrochloric acid (3 M). The solid which crashed out was collected by filtration, washed twice with water, methanol and diethyl ether, dried under reduced pressure to afford 0.25 g (75% yield) of 6-carbamoyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Cl[CH2:25][C:26]1([CH3:30])[CH2:29][O:28][CH2:27]1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]3([CH3:30])[CH2:29][O:28][CH2:27]3)=[CH:23][C:6]1=2
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC1(CCl)COC1
Product: CC1(COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)COC1

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 3-chloromethyl-3-methyloxetane.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C.C(Cl)Cl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(-c2ncco2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Temperature: 110 °C
Yield: 76.6 %

Procedure:
A solution of 4-(2-oxazolyl)phenol (15.7 g, 97 mmol) in DMF (120 mL) was treated with cesium carbonate (41 g, 126 mmol) and 4-fluorobenzaldehyde (13.3 g, 107 mmol). The reaction was heated at 110° C. for 2.5 hours. The reaction mixture was cooled and poured onto a mixture of ice and water. The product was isolated by extraction with methylene chloride (3×). The combined organic layers were washed with water and brine, dried, and concentrated. The residue was recrystallized from aqueous ethanol to give 19.7 g of 4-[4-(2-oxazolyl)phenoxy]-benzaldehyde.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([C:18](=[NH:21])[NH:19][OH:20])=[N:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([O:25]CC)=[O:24])[O:3]1.[Li+].[OH-]>C1COCC1.CO>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([C:18](=[NH:21])[NH:19][OH:20])=[N:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([OH:25])=[O:24])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C(=N)NO)s3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2nnc(C(=N)NO)s2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude ethyl 2-(1-hydroxy-6-(5-(N-hydroxycarbamimidoyl)-1,3,4-thiadiazol-2-yloxy)-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate was dissolved in a mixture of THF and MeOH (1:1, 5 ml) and then treated with aqueous LiOH solution (200 mg in 5 mL water). After stirring at room temperature for one hour, the reaction mixture was evaporated, acidified with 1N HCl to pH 3 and then concentrated. HPLC purification gave desired product as white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (b, 1H), 10.3 (b, 1H), 9.20 (b, 1H), 7.41 (d, J=2Hz, 1H), 7.28 (d, J=1.6 Hz, 1H), 5.48 (dd, J=9.2, 2 Hz, 1H), 4.07 (b, 2H), 3.00 (dd, J=15.6, 2.4 Hz, 1H), 2.27 (s, 3H), 2.10 (dd, J=15.6, 9.2 Hz, 1H). MS (ESI) m/z=363 [M−H]+.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[CH2:21]([O:20][C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=[C:17]([Br:19])[CH:16]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 93.3 %

Procedure:
To an ice-cold solution of 1-benzoyl-3-(3-benzyloxy-5-bromo-phenyl)thiourea (33.0 g, 74.70 mmol) in THF (500.0 mL) was added a solution of NaOH (15.0 g, 375.0 mmol) in H2O (180.0 mL). The resulting reaction mixture was stirred at 65° C. for 15 h. The reaction mass was then cooled to room temperature, added water and extracted with EtOAc (3×1.0 L). The combined organics was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the desired compound (23.50 g, 94%) that was carried forward to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[NH2:33][CH2:34][CH2:35][CH:36]([OH:38])[CH3:37].NCCCCO>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:33][CH2:34][CH2:35][CH:36]([OH:38])[CH3:37])[N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CC(O)CCN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1
Agent: NCCCCO
Product: CC(O)CCNc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1

Procedure:
The compound was prepared from 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-urea and 4-amino-butan-2-ol as described in example 10 for 4-amino-butan-1-ol instead.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1Cl>ClC1C=CC=CC=1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[O:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(F)c(O)cc1F
Reactant: Clc1ccncc1Br
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1cc(F)c(Oc2ccncc2Br)cc1F
Temperature: 145 °C
Yield: 37.8 %

Procedure:
2,5-Difluoro-4-nitro-phenol (1.739 g, 9.93 mmol) and 3-bromo-4-chloro-pyridine (0.637 g, 3.31 mmol) were dissolved in chlorobenzene (6 ml) and heated at 145° C. overnight. The solvent was removed under reduced pressure and the residue partitioned between EtOAc and 10% K2CO3 (aq). The mixture was extracted with EtOAc (2×). The combined organic extracts were washed with 10% K2CO3 (aq) and brine, dried, evaporated and purified by silica gel chromatography (hexanes/EtOAc) to yield 3-bromo-4-(2,5-difluoro-4-nitrophenoxy)pyridine (414 mg, 38% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.84 (s, 1H), 8.51-8.45 (m, 2H), 7.82-7.78 (m, 1H), 7.22 (d, 1H); MS (ESI) m/z: 331.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:12][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[C:21]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([Cl:19])=[N:25][CH:24]=2)[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH3:11]
Reactant: Cn1ncc2c(N)cc(Br)cc21
Reactant: CS(=O)(=O)Nc1cc(B(O)O)cnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ncc2c(N)cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc21
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 29.9 %

Procedure:
6-Bromo-1-methyl-1H-indazol-4-amine (340 mg), sodium carbonate (638 mg) and Pd(dppf)Cl2 (110 mg) were weighed to a 10-20 ml microwave vial. {6-Chloro-5-[(methylsulfonyl)amino]-3-pyridinyl}boronic acid (377 mg) dissolved in 1,4-dioxane (6 ml) was added followed by water (6 ml). The reaction was heated for 15 min at 120° C. in the microwave. The reaction was passed through a 2 g silica cartridge, washing with methanol. The solvent was evaporated under nitrogen blow down. The residue was purified on the ISCO companion using a 40 g silica cartridge and a gradient of 2-8% methanol in DCM (containing 1% ammonia) over 15 mins at 40 ml/min. Product-containing fractions were combined and dried down to give title compound (158 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH2:15])=[O:5].CCN(C(C)C)C(C)C.[Cl:25][C:26]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl.C(OCC)(=O)C>[Cl:25][C:26]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:15][C@H:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=2)[CH2:11][CH2:10]1)=[O:29]
Reactant: O=C(Cl)c1cccc(F)c1Cl
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cccc(F)c1Cl)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
(3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (0.2 mmol, 1 eq) was dissolved in dichloromethane, and DIPEA (2.5 eq) and 2-chloro-3-fluorobenzoic acid chloride (1.2 eq) were added under a protecting gas atmosphere at 0° C. The reaction mixture was stirred for 2 h at RT. Then the reaction mixture was diluted with ethyl acetate, washed 1× with sat. NaHCO3 solution, 1× with 10% ammonium chloride solution and 1× with sat. NaCl solution, dried over magnesium sulfate and purified by column chromatography (silica gel, cyclohexane:ethyl acetate 4:1). Yield: 92%
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].[Cl:19][C:20]1[CH:25]=[C:24]([N+]([O-])=O)[CH:23]=[CH:22][N:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([O:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])[CH:23]=[CH:22][N:21]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2ccnc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.48 gm (0.018 mol) of potassium carbonate were added in portions to a stirred solution of 2.95 gm (0.015 mol) of 2-chloro-4-trifluoromethyl-phenol and 2.2 gm (0.015 mol) of 2-chloro-4-nitro-pyridine in 10 ml of dimethylformamide, and the mixture was stirred first for 1 hour at room temperature and then for 11/2 hours at 80° C. Thereafter, the reaction mixture was poured into ice water and the aqueous mixture was extracted with chloroform. The organic phase was separated, washed with 2N sodium hydroxide and with water, dried with sodium sulfate and evaporated, yielding the title compound as a colorless oil.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: CC(C)(C)C(=O)Cl
Agent: Br
Solvent: c1ccncc1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
1 g (0.0033 mol) of L-alanyl-L-proline ethylamide hydrobromide was dissolved in 20 ml of dry pyridine and 0.45 ml of pivaloyl chloride was added. The mixture was stirred for 1 hour at room temperature and then the pyridine was removed by evaporation. The oil was triturated with toluene, re-evaporated and then partitioned between chloroform and saturated brine. The chloroform layer was separated and dried over magnesium sulphate, filtered off and evaporated to a clear oil which crystallised on the addition of petrol. The solid was filtered off, washed with petrol and dried to yield 0.4 g (40%) of N-pivaloyl-L-alanyl-L-proline ethylamide of melting point 94°-96° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH2:20].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1.CCOC(C)=O>[Cl:13][C:4]1[CH:3]=[C:2]([NH:20][CH2:19][C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: NCc1cccs1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(Cl)cc1NCc1cccs1
Yield: 100.4 %

Procedure:
A solution of ethyl 4,6-dichloronicotinate (1.14 g, 5.18 mmol), 2-thiophenemethylamine (0.530 mL, 5.17 mmol) and DIEA (1.80 mL, 10.3 mmol) in NMP (10 mL) was stirred at 90 C for 18 h. Water and EtOAc were added. The organic phase was washed with water, then was dried over Na2SO4, concentrated in vacuo to give ethyl 6-chloro-4-(thiophen-2-ylmethylamino)nicotinate as an oil (1.54 g).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9](=[O:28])[CH:10]([O:25][CH2:26][CH3:27])[N:11]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)=[N:12]2)=[CH:5][CH:4]=1)#[N:2]>C(O)C.[Pd]>[NH2:22][C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][N:11]([CH:10]([O:25][CH2:26][CH3:27])[C:9]([NH:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=3)=[O:28])[N:12]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)n1ccc(-c2cccc([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)n1ccc(-c2cccc(N)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To a stirred suspension of 10% Pd/C (214 mg) at r.t. in ethanol (4 ml) under an argon atmosphere was added of (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-[3-(3-nitro-phenyl)-pyrazol-1-yl]-acetamide (2.1 g). The mixture was stirred at r.t. under a hydrogen atmosphere for 18 h. The catalyst was filtered over a celite pad and the cake was washed with ethanol. The filtrate was concentrated. The crude product was purified by chromatography (silica gel, gradient cyclohexane=>EtOAc) to give (RS)-2-[3-(3-amino-phenyl)-pyrazol-1-yl]-N-(4-cyano-benzyl)-2-ethoxy-acetamide (1.0 g) as off-white solid. MS 376.5 ([M+H]+)
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH:17]=[O:18].[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:2]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]=2[CH:17]=[O:18])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ncccc12
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2c(C=O)c3cccnc3n2-c2ccccc2)CC1
Temperature: 110 °C
Yield: 99.4 %

Procedure:
A solution of 2-chloro-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (210 mg, 0.818 mmol) in 1,4-dioxane (10 mL) is treated with [1,4]diazepane-1-carboxylic acid tert-butyl ester (0.80 mL, 4.11 mmol) and the resulting yellow solution is heated to 110° C. under a reflux condenser for 19.5 hours. The reaction mixture is evaporated to give an orange oil. The residue is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane, increasing to dichloromethane:methanol (99:1). Fractions containing the product are combined and the solvent evaporated to give 342 mg of 4-(3-formyl-1-phenyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester as a yellow orange glass (99.5% yield). MS: m/e 421 (M+H), 443 (M+Na), 365 (M-C4H8+H), 343(M-C5H8O2+Na), 321(M-C5H8O2+H). 1H NMR (300 MHz, CDCl3): 10.23 (1H, s), 8.49 (1H, d), 8.22 (1H, dd), 7.64-7.48 (3H, m), 7.42 (2H, d), 7.19 (1H, dd), 3.50-3.29 (8H, m), 1.65-1.52 (2H, m), 1.44 (9H, s).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=C1C=CC(O)N1
Product: O=C1C=CC(OCc2ccccc2)N1
Temperature: 60 °C

Procedure:
A mixture of 8 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 130 cm3 of benzyl alcohol and 4 g of Amberlite IR 120 H is heated for 3 hours at 60° C. The benzyl alcohol is distilled off at 65° C. under 0.3 mbar. then is drawn off under azeotropic form first with water and then with benzene. 13.6 g of the expected product is obtained, which is unstable on distilling.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([CH2:20][C:21]([OH:23])=[O:22])=[C:12]2[CH3:24])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:25]#[N:26].[CH3:27]OC(=O)CC1C2C(=NC=CC=2)NC=1CC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([CH2:20][C:21]([OH:23])=[O:22])=[C:12]2[CH2:24][CH3:27])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:25]#[N:26]
Reactant: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(C#N)c1
Reactant: CCc1[nH]c2ncccc2c1CC(=O)OC
Product: CCc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(C#N)c1

Procedure:
The titled compound is prepared analogously to [1-(4-chloro-3-cyano-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid (Example 103) by replacing (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester with (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (Intermediate 87c). (MH+ 404)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.Cl.[OH:21][C:22]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:22]=4[OH:21])[CH2:27]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2cccnc2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccnc3)nc3ccccc13)C2
Yield: 16 %

Procedure:
Reaction of 2-(3-pyridinyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 84 (16% yield) as a light yellow solid. 1H NMR (300 MHz, CD3OD) δ 2.82 and 3.08 (2t, 2H), 3.58 and 4.17 (2t, 2H), 3.83 and 3.89 (2s, 3H), 4.45 and 5.03 (2s, 2H), 6.29 and 6.79 (2d, 1H), 6.71 and 6.92 (2d, 1H), 7.60-8.25 (m, 5H), 8.71-8.72 (m, 1H), 8.92-9.05 (m, 1H), 9.68 and 9.73 (2s, 1H); MS (ESI) m/z 413 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[N:17]([C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)[C:16]1=[O:38])([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:3].[CH:39]1(B(O)O)[CH2:41][CH2:40]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[N:17]([C:31]2[CH:36]=[CH:35][C:34]([CH:39]3[CH2:41][CH2:40]3)=[CH:33][CH:32]=2)[C:16]1=[O:38])([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:3]
Reactant: OB(O)C1CC1
Reactant: CC(C)(N[C@@H]1C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(Br)cc2)C1=O)c1ccc(C(F)(F)F)nc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C3CC3)cc2)C1=O)c1ccc(C(F)(F)F)nc1
Yield: 90.4 %

Procedure:
Dissolve (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-1-(4-bromo-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-2-one (1.25 mmoles; 750 mg), cyclopropylboronic acid (1.62 mmoles; 139 mg), tribasic potassium phosphate N-hydrate (4.36 mmoles; 925 mg), and tricyclohexylphosphine (124.51 μmoles; 34 mg) in toluene (5 mL) and water (275 μL) and degas the solution for 5 minutes then place under a nitrogen atmosphere. Add Pd(OAc)2 (62 μmoles; 14 mg) and heat the mixture at 90° C. overnight. Dilute with ethyl acetate (50 mL) and filter through celite. Wash the filtrate with water, 1N HCl, saturated aqueous sodium bicarbonate, brine, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to a brown residue. Purify the residue by flash chromatography on silica with gradient 0->50% ethyl acetate in hexane to afford the title compound (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-cyclopropyl-phenyl)-pyrrolidin-2-one (1.13 mmoles; 639.00 mg; 91.07% yield). LC/MS m/z 564.2 (M+1), Tr=4.87 min (Method 3).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.C[O:32][C:33]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]([O:46]C)=[C:38]2[C:34]=1[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][OH:60])=[CH:55][CH:54]=1)[CH2:37]2>O>[CH3:43][O:42][C:41]1[C:33](=[O:32])[C:34]2[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:58]=[CH:57][C:56]([CH2:59][OH:60])=[CH:55][CH:54]=3)[CH2:37][C:38]=2[C:39](=[O:46])[C:40]=1[O:44][CH3:45]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(CO)cc1)C2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(CO)cc3)C2)C1=O
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
A water (1.0 ml) solution of CAN (1.24 g, 2.27 mmols) was dropwise added to an acetonitrile (8.0 ml) solution of 4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]phenylmethanol (370 mg, 0.888 mmols), with cooling with ice, and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 2:1) followed by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (150 mg) as crystals.