Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C(O)C.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[CH2:18][C:19]([O:21]CC)=[O:20])=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[CH2:18][C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1cccc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2cccc(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
40 g sodium hydroxide was dissolved in 1000 ml water and 1000 ml 95% ethanol was added. They were mixed. Then, 50 g ethyl (7-methoxy-1-naphthyl)-acetate was added into above-mentioned mixture solution and the mixture solution was stirred for 3 hours at room temperature. The reaction was subsequently stopped and vacuum evaporated to remove ethanol, resulting in brown-red liquid. The liquid was washed with 300 ml×2 ethyl acetate prior to adding 30 ml 95% ethanol into the aqueous layer. The pH was adjusted to 2 by adding concentrated hydrochloric acid in drops with rapid stirring, resulting in a large amount of light brown solid being precipitated. They were filtered and dried to obtain 32 g product with mp of 154-156° C. The content measured by HPLC is 98.48%, and the yield is 72%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:25][O:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:27]=4[O:26][CH3:25])[CH2:32]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=C(O)c1nc(-c2cccc(C(F)(F)F)c2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3cccc(C(F)(F)F)c3)nc3ccccc13)C2
Yield: 12 %

Procedure:
Reaction of 2-(3-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 54 (12% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.74 and 2.99 (2t, 2H), 3.52 and 4.04 (2t, 2H), 3.68-3.82 (4s, 6H), 4.43 and 4.95 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.75-7.88 (m, 2H), 7.93-8.04 (m, 2H), 8.11-8.17 (m, 1H), 8.21-8.26 (m, 1H), 8.74-8.85 (m, 2H); MS (ESI) m/z 494 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([C:33]2[N:41]3[C:36]([CH:37]=[N:38][C:39](O)=[N:40]3)=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH:21][C:39]2[N:38]=[CH:37][C:36]3=[CH:35][CH:34]=[C:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=4)[N:41]3[N:40]=2)[CH:18]=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc(N)ccc1Cl
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc(Nc2ncc3ccc(-c4cccc(S(C)(=O)=O)c4)n3n2)ccc1Cl

Procedure:
This example was prepared by using (S)-2-(5-Amino-2-chloro-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Med. Chem. 2007, 50, 4353) and 7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c. 1H-NMR (CDCl3) δ 8.7 (brs, 1H), 8.6 (m, 1H), 8.4 (d, J=8.0 Hz, 1H), 8.0 (d, J=8.0 Hz, 1H), 7.7 (t, 1H), 7.5-7.0 (m, 5H), 4.1-3.9 (m, 3H), 3.5-3.2 (m, 2H), 3.0 (s, 3H), 2.2 (m, 3H), 1.9 (m, 1H); LC/MS (ESI+): 598 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[N:10][C:2]=1[NH2:1]
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)nc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
A suspension of 2-amino-6-chloronicotinic acid (500 mg, 2.90 mmol) and is potassium carbonate (441 mg, 3.19 mmol) in DMF (5 ml) was heated to reflux. The reaction mixture was cooled to room temperature and 273 μl of iodomethane (4.35 mmol) were added. The mixture was then refluxed under stirring for 18 h. After subsequent cooling, the mixture was finally filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethyl acetate/petroleum ether=95/5). The isolated 2-amino-6-chloronicotinic acid methyl ester was obtained in 54% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Fc1ccc(S)c(Cl)c1
Reactant: Fc1ccc(I)c(Br)c1
Product: Fc1ccc(Sc2ccc(F)cc2Br)c(Cl)c1

Procedure:
Prepared from 2-chloro-4-fluoro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[OH-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:25][CH2:26][NH2:27]>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:22]([O:21][CH3:20])[CH:23]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: COc1ccc(CCN)cc1OC
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)Cc2cccc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Bromo-phenyl)-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-acetamide (41) was prepared as follows: A solution of 3-bromo-phenylacetic acid (2.0 g, 9.3 mmol) and oxalyl chloride (36.4 g, 0.287 mol) in 80 mL of benzene was refluxed for 6 h. The solution was evaporated with benzene 3 times and dried in vacuum. A solution of 3-bromo-phenylacetic acid (1.1 eq.) in CH2Cl2 was added to mixture of 100 mL of 1N NaOH and solution of 3,4-di-methoxy-phenethylamine (1.31 g, 7.22 mmol) in 100 mL of CH2Cl2. The reaction mixture was stirred overnight at r.t. Another portion of acid chloride (0.1 eq.) in 10 mL of CH2Cl2 was added and stirred for 1 h. Organic phase was separated, washed with 1N HCl, 1N NaOH, water, dried over Na2SO4, filtered and evaporated. A residue was crystallized from EtOAc-hexanes mixtures. Yield is 2.59 g (95%).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:10])=[CH:28][CH:27]=1
Reactant: O=C(/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1)NCCCCc1cccnc1
Yield: 93.8 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (15 g) and 3-pyridinebutanamine (5,53 g) in tetrahydrofuran (60 mL) was stirred for 1.5 hours at room temperature and was worked up in the usual manner. The crude amide was crystallized from ethyl acetate-hexane (2×) to give 14.45 g of (E)-5,5-bis(4-fluorophenyl)-N-[4-(3-pyridinyl) butyl]-2,4-pentadienamide mp 155°-156° C. Anal. Calculated for C26H24F2N2O: C, 74.62; H, 5.78; F, 9.08; N, 6.69 Found: C, 74.55; H, 5.87; F, 9.33; N, 6.60.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][C:12]3([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:11][C:10]2=[O:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][C:13]12[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=1)[NH:11][C:10](=[O:27])[N:9]2[C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(CC23CCCC=C2N(c2cc(Cl)cc(Cl)c2)C(=O)N3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC12CCCCC1(Cc1ccc(C#N)cc1)NC(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[1-(3,5-Dichlorophenyl)-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (150 mg) (0.38 mmol) in DMF (5 ml) was carefully dropped on a suspension of NaH 60% (18.2 mg) (1.2 eq) in DMF (5 ml) at RT. The reaction mixture was stirred for 1 h at RT, then ethyl bromoacetate (0.052 ml) (1.2 eq) was added. After one night, the reaction mixture was poured on water and extracted with tBuOMe. The organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was purified on SiO2 chromatography (eluent EtOAc/cyclohexane—2/8) to give [7a-(4-Cyano-benzyl)-3-(3,5-Dichlorophenyl)-2-oxo-2,3,5,6,7,7a-hexahydro-benzimidazol-3a-yl]-acetic acid ethyl ester (46.5 mg) as a white solid. 1H NMR (CDCl3): 7.55 (2H, d), 7.25 (2H, d), 7.1 (1H, m), 6.8 (2H, m), 5.0 (1H, m), 4.45 (1H, d), 4.2 (2H, q), 3.75 (1H, d), 3.05 (1H, d), 2.90 (1H, d), 2.5-2.1 (2H, m), 2.1-1.8 (4H, m), 1.25 (3H, t).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[C:12]([NH2:26])[N:11]=2)=[CH:6][C:5]=1[Cl:27]>C1COCC1>[NH2:26][C:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([Cl:27])[CH:6]=2)[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[C:14]([CH3:25])[N:13]=1
Reactant: COC(=O)c1ccc(-c2nc(N)nc(C)c2C#Cc2ccc(N)nc2)cc1Cl
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 1.24 g (3.1 mmol) 4-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-chloro-benzoic acid methyl ester using 4.7 mL (4.7 mmol) 1 N NaOH in 22 mL THF. The product precipitates and is isolated by filtration. The product is washed with THF and diethylether. Yield: 1.13 g (95%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([CH3:18])[CH:5]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)CCC.[Cl-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=1[CH3:18]
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-c2ccco2)c(C)c1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
To a stirred solution of trifluoromethanesulfonic acid 4-acetyl-2methylphenyl ester (1.19 g, 4.2 mmol) in 1,4-dioxane (40 mL) was added 2-(tributylstannyl)furan (1.81 g, 5.05 mmol), lithium chloride (0.45 g, 10.5 mmol) and tetrakis(triphenylphosphine)palladium (0.49 g, 0.42 mmol) under nitrogen. The mixture was heated at reflux temperature for 2 hours, and cooled down to room temperature. The reaction mixture was diluted with water and the whole was extracted with diethylether. The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1/10) to give title compound (0.845 g, quant).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:24][C:25](=[O:29])[CH2:26][CH2:27][NH2:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25](=[O:29])[CH2:26][CH2:27][NH:28][C:11]([CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:14]([NH:28][CH2:27][CH2:26][C:25]([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:29])=[O:16])=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NCCC(=O)OCc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-L-aspartic acid is coupled with two equivalents of β-alanine benzyl ester to give N,N'-[[(S)-(1-t-butoxyformamido)ethylene]dicarbonyl]di-β-alanine dibenzyl ester, m.p. 109°-110° C.
Reaction SMILES: [N:1]#CBr.C(N(C(C)C)CC)(C)C.C(Cl)(Cl)Cl.[CH3:17][N:18]1[C:22]2[CH2:23][CH2:24][C:25]3[C:32]4([CH3:35])[CH:33]([CH3:34])[CH:19]1[CH2:20][C:21]=2[C:26]=3[CH:27]=[CH:28][CH2:29][N:30]=[CH:31]4>C(=O)(O)[O-].[Na+]>[C:17]([N:18]1[C:22]2[CH2:23][CH2:24][C:25]3[C:32]4([CH3:35])[CH:33]([CH3:34])[CH:19]1[CH2:20][C:21]=2[C:26]=3[CH:27]=[CH:28][CH2:29][N:30]=[CH:31]4)#[N:1]
Reactant: N#CBr
Reactant: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C#N
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To a stirred solution of 6.81 g of cyanogen bromide, 4.7 ml of diisopropylethylamine, and 142 ml of chloroform was added, at room temperature with stirring, a solution of 13.7 g of 1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 414 ml of chloroform. The mixture was heated at reflux for 2.6 hr, cooled to room temperature, diluted with aqueous sodium bicarbonate solution, and the layers were separated. The organic layer was washed with sodium bicarbonate solution. The combined aqueous layers were extracted with ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, and filtered. Concentration of the filtrate followed by purification by flash chromatography (silica gel, 2% triethylamine/ethyl acetate) afforded 13.5 g (95%) of 3-cyano-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)[CH3:2].[C:19]1([SiH2]C2C=CC=CC=2)C=CC=C[CH:20]=1>O1CCCC1.C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Rh]>[CH2:1]([N:4]([CH2:5][C@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:19][CH3:20])[CH3:2]
Reactant: CC(=O)NC[C@H]1COCCN1C(=O)OC(C)(C)C
Reactant: c1ccc([SiH2]c2ccccc2)cc1
Agent: [Rh]
Agent: C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C[C@H]1COCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl 3-((N-ethylacetamido)methyl)morpholine-4-carboxylate (INTERMEDIATE 86A, Step 2, 0.04 g, 0.14 mmol) and diphenylsilane (0.052 ml, 0.28 mmol) in tetrahydrofuran (1.345 ml) at rt was added carbonyltris(triphenylphosphine)rhodium(I)hydride (6.42 mg, 6.98 mol). After a brief surge of gas evolution, the now yellow reaction was stirred for 30 min and then quenched with 1N aqueous hydrogen chloride. The mixture was extracted with ether, and the aqueous layer was basified with 50% aqueous sodium hydroxide. The aqueous layer was the extracted with ethyl acetate (×4), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (S)-tert-butyl 3-((diethylamino)methyl)morpholine-4-carboxylate (0.038 g, yield: almost quantitative) (INTERMEDIATE 86A, Step 3).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[C:31]4[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:42].O1CCOCC1>ClCCl>[ClH:42].[CH2:36]([O:35][CH2:34][CH2:33][N:32]1[C:31]2[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=2[N:29]=[C:28]1[N:24]1[CH2:25][CH2:26][CH2:27][N:21]([CH2:20][CH2:19][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:22][CH2:23]1)[CH3:37]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)C3)CC2)nc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reaction time: 8 h

Procedure:
Combine 1-t-butoxycarbonyl-3-(2-(4-(1-(2ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (5.0 g) and dichloromethane (50 mL). Add a solution of hydrochloric acid in dioxane (10 mL, 4 M, 40 mmol). After 8 hours, evaporate in vacuo to give 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt.
Reaction SMILES: C(O[C:6]([N:8]1CC[CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.[C:31]1(NCCN)[CH:36]=[CH:35]C=[CH:33][CH:32]=1>>[C:6]1([NH:8][CH2:9][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCNc1ccccc1
Product: O=C(NCCNc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using N-phenylethylenediamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 378 (M+H) 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.00 (1H, d, J=5.66 Hz) 7.62 (1H, d, J=5.42 Hz) 7.45 (1H, d, J=5.37 Hz) 7.25 (1H, d, J=3.56 Hz) 7.07 (2H, dd, J=8.66, 7.30 Hz) 6.86 (1H, d, J=5.66 Hz) 6.51-6.67 (4H, m) 3.55 (2H, t, J=6.47 Hz) 3.25-3.30 (2H, m)
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[OH-].[K+].[CH3:21]I>O1CCCC1>[CH2:17]([O:16][C:10]1[CH:9]=[C:8]([C:2]2([CH3:1])[O:6][C:5](=[O:7])[N:4]([CH3:21])[CH2:3]2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH3:18]
Reactant: CCOc1cc(C2(C)CNC(=O)O2)ccc1OC
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C2(C)CN(C)C(=O)O2)ccc1OC
Yield: 37.9 %

Procedure:
500 mg (2.0 mmol) of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-2-oxazolidinone, 125 mg (2.22 mmol) of potassium hydroxide, and 0.167 ml (2.38 mmol) of methyl iodide were stirred in 4 ml of tetrahydrofuran for 4 hours at room temperature. The process was continued analogously to Example 8, thus obtaining 201 mg of 5-(3-ethoxy-4-methoxyphenyl)-3,5-dimethyl-2-oxazolidinone as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:17]3[CH:18]=[C:19]([C:22]([OH:24])=O)[S:20][CH:21]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][NH:3]1.CC[N:27]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:27])=[O:24])[S:20][CH:21]=3)=[N:9][N:10]([CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: O=C(O)c1cc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cs1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cs1
Yield: 86.9 %

Procedure:
A solution of 4-(4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (105 mg) obtained in Example 23, HOBt ammonium salt (139 mg) and EDCI hydrochloride (175 mg) in DMF (15 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol) to give the title compound (91 mg).
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:26])[NH:17][C:18]3[C:23]/2=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)/[CH:9]=1.[CH:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:25])[NH:17][C:16](=[O:26])/[C:15]/2=[C:10]1\[CH:9]=[C:8]([C:32]2[CH:33]=[CH:34][C:29]([CH:27]=[O:28])=[CH:30][CH:31]=2)[C:12]([CH3:14])([CH3:13])[O:11]\1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1Br
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(C=O)cc1
Temperature: 80 °C

Procedure:
To 10 mL of 1,4-dioxane was added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (85 mg, 0.25 mmol), 4-formylphenylboronic acid (45 mg, 0.30 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol), 2M Na2CO3 aqueous solution (0.5 mL, 1.0 mmol). The mixture was heated at 80° C. under N2 for 30 minutes. After cooling to room temperature, the mixture was diluted with EtOAc (80 mL). The EtOAc solution was washed with brine (2×50 mL), dried over Na2SO4, and concentrated to give 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as the crude product, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]#[C:16][C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:41]1[CH2:46][CH2:45][CH:44]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH2:43][CH2:42]1>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:41]1[CH2:42][CH2:43][CH:44]([N:47]3[CH2:51][CH2:50][CH2:49][C:48]3=[O:52])[CH2:45][CH2:46]1)=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1CCCN1C1CCNCC1
Reactant: O=C(O)C#CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.5 %

Procedure:
After 3-((6-chloronaphthalen-2-yl)sulfonyl)propinoic acid (0.30 g), HOBt (0.23 g) and WSC (0.29 g) were dissolved in DMF (10 mL), 1-(piperidin-4-yl)-2-pyrrolidinone (0.17 g) and triethylamine (0.10 g) were added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate and an aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound (0.17 g, 39%) as a colorless powder.