Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:16]([NH2:18])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)#[N:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:16](/[N:18]=[CH:29]/[N:30]([CH3:32])[CH3:31])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)#[N:2]
Reactant: N#Cc1c(N2CCOC(CO)C2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/C(=O)c1sc(N2CCOC(CO)C2)c(C#N)c1-c1ccc(Cl)cc1Cl
Yield: 99.7 %

Procedure:
A mixture of 4-cyano-3-(2,4-dichlorophenyl)-5-[2-(hydroxymethyl)morpholin-4-yl]thiophene-2-carboxamide (115 mg, 0.279 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (3.44 mL, 0.025 mol) was flushed with argon and then irradiated in microwave at 160° C. for 60 min. The reaction mixture was concentrated to give 4-cyano-3-(2,4-dichlorophenyl)-N-[(1E)-(dimethylamino)methylene]-5-[2-(hydroxymethyl)morpholin-4-yl]thiophene-2-carboxamide (130 mg, 99%). LCMS: (FA) ES+ 467. To the above intermediate in AcOH (4.3 mL, 0.076 mol) was added hydrazine hydrate (100 mg, 0.003 mol). The mixture was flushed with argon and then irradiated in microwave at 120° C. for 20 min. The mixture was concentrated to remove the solvent. The residue was purified using ISCO chromatography on silica gel, elution 1:1 hexane-ethyl acetate to ethylacetate to afford 4-(2,4-dichlorophenyl)-2-[2-(hydroxymethyl)morpholin-4-yl]-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (90 mg, 70%). LCMS: (FA) ES+ 436, 1H NMR (400 MHz, d4-methanol) δ: 8.28 (s, 1H), 7.55 (d, 1H), 7.41 (dd, 1H), 7.34 (d, 1H), 4.12-3.72 (m, 5H), 3.68-3.61 (m, 2H), 3.30-3.20 (m, 1H), 3.12-3.02 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=2)=[N:17][N:16]=[N:15]1.C([O-])(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]3[NH:17][N:16]=[N:15][N:14]=3)=[CH:26][CH:27]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2ccccc2n1
Yield: 37.5 %

Procedure:
To 50 mL of tetrahydrofuran were added 2,4-dichloroquinazoline (0.30 g). N-[[-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl amine hydrochloride (0.434 g) and 2.0 g of sodium acetate. The resulting suspension was stirred at room temperature for 53 hours at which time all the THF was removed by evaporation. The residue was purified by silica gel chromatography to yield 0.234 g of the desired product. (38%). The product was characterized as its sodium salt: 1H NMR (DMSO-d6, 400 MHz) δ9.30 (t, J=5.9 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 7.79 (m, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.52 (m, 2H), 7.32 (m, 3H), 7.18 (d, J=8.2 Hz, 2H), 7.07 (d, J=8.2 Hz, 2H), 4.72 (d, J=5.8 Hz, 2H); negative FAB MS m/e 412 (M-Na)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14]2)=[O:10].O>CN(C)C=O>[N:1]1([CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C1Cc2cc(C(=O)CBr)ccc2N1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Cc2cc(C(=O)CN3CCCCC3)ccc2N1
Yield: 49.1 %

Procedure:
A solution of piperidine (0.39 ml, 3.9 mmole) and 5-(2-bromoacetyl)-2-indolinone (500 mg, 1.97 mmole) in N,N-dimethylformamide (15 ml) was stirred at room temperature 4 h then was poured into water (50 ml) and washed with dichloromethane (250 ml), the organic solution was washed with water several times and dried over sodium sulfate. After evaporation of the solvent the residue was chromatographed on siiica-gel using ethyl acetate as eluant to give 5-(2-piperidin-1-yl-acetyl)-2-indolinone (250 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:20])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5]
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(C(=O)O)c3)ccc12
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 3-[2-(2,4-dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-benzoic acid (40 mg, 0.09 mmol) in dichloromethane (2 mL) was added 2-methoxyethylamine (0.02 mL, 0.19 mmol), EDCl (20 mg, 0.1 mmol), DMAP (1 mg, 0.01 mmol), and N,N-diisopropylethylamine (0.02 mL, 0.1 mmol). The reaction mixture was stirred at rt overnight, then concentrated in vacuo and purified by prep-HPLC to afford the desired product (11 mg, 25%). 1H-NMR (CDCl3) δ 8.05 (t, J=1.8 Hz, 1H), 7.77-7.75 (m, 3H), 7.69 (m, 1H), 7.60 (dd, J=8.3, 1.0 Hz, 1H), 7.51 (m, 2H), 7.47 (m,1H), 7.40 (ddd, J=8.2, 1.9, 0.5 Hz, 1H), 6.62 (t, J=4.5 Hz, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.40 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=2[CH3:30])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=4[CH3:30])[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(Cl)cc3)CC2)CC1

Procedure:
Example 89 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.40–7.32 (m, 7H), 7.08 (d, 1H, J=8.4 Hz), 5.70 (br s, 1H), 3.27 (dd, 2H, J=6.4, 12.4 Hz), 2.88 (d, 2H, J=11.6Hz), 2.64 (m, 1H), 2.53 (m, 1H), 2.31 (t, 2H, J=6.8 Hz), 2.28 (s, 3H), 1.99 (dt, 2H, J=2.8, 11.2 Hz), 1.67–1.60 (m, 8H), 1.27 (d, 6H, J=6.8 Hz), 1.03 (dd, 2H, J=4.0, 6.8 Hz); ESMS m/e: 496.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([C:13]3[O:17][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]4)=[N:15][C:14]=3[C:25]([F:28])([F:27])[F:26])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:46])[CH:44]=[CH2:45]>C(#N)C>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:46])[CH2:44][CH2:45][N:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([C:13]3[O:17][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]4)=[N:15][C:14]=3[C:25]([F:27])([F:28])[F:26])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ccc4c3)o2)C1
Reactant: C=CC(=O)Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(ccn4CCC(=O)Nc4ccccc4F)c3)o2)C1
Temperature: 25 °C
Reaction time: 30 h
Yield: 7.6 %

Procedure:
To a solution of compound 44 (0.080 g, 0.204 mmol) and cesium carbonate (0.133 g, 0.408 mmol) in anhydrous acetonitrile (1.0 mL) at room temperature was added N-(2-fluorophenyl)acrylamide (C-4) (0.101 g, 0.612 mmol) in one portion. The reaction mixture was stirred at room temperature for 30 h, then additional N-(2-fluorophenyl)acrylamide (C-4) (0.168 g, 1.02 mmol) was added, and the reaction mixture was heated at 50° C. for 24 h. The reaction mixture was filtered over a celite pad, washed with methylene chloride (50 mL) and concentrated. Purification of the crude residue by silica gel chromatography (eluant gradient: 100% methylene chloride to 100% EtOAc) followed by C18 reverse phase chromatography (H2O:CH3CN eluant gradient) gave 8.7 mg (6.8% yield) of N-[1-(3-(2-fluorophenylamino)-3-oxopropyl)-1H-indol-5-yl]-2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (71) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.05 (br s, 1H), 10.05 (br s, 1H), 9.82 (br s, 1H), 7.88 (m, 1H), 7.85 (m, 1H), 7.53 (d, 1H, J=9.1 Hz), 7.37 (m, 1H), 7.24 (m, 1H), 7.15 (m, 2H), 6.42 (m, 1H), 4.49 (br t, 2H, J=6.6 Hz), 4.12 (m, 2H), 3.05 (t, 1H, J=11.5 Hz), 2.92 (t, 2H, J=6.6 Hz), 2.74 (t, 1H, J=11.9 Hz), 1.78 (m, 3H), 1.54 (m, 1H), 1.16 (m, 1H), 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 558.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[NH:35][CH:36]=[N:37]2.C(NC(C)C)(C)C.O>C(#N)C>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([C:33]3[N:41]=[CH:40][N:39]=[C:38]4[C:34]=3[NH:35][CH:36]=[N:37]4)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: O
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)c1ncnc2nc[nH]c12

Procedure:
A solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-heptanamine (5.30 g, 12.2 mmol), 6-chloropurine (1.90 g, 12.3 mmol), and diisopropylamine (3.00 mL, 17.2 mmol) in acetonitrile (50 mL) was heated to mild reflux for 18 hours, and then cooled and poured into water (200 mL). This was extracted with methylene chloride (2×200 mL), and the extracts were combined, dried over anhydrous potassium carbonate, filtered and evaporated. The residue was separated by flash chromatography (ethyl acetate) to afford the title product as a solid, m.p. 58°-60° C. 1H NMR (CDCl3): 10.66 (2H, br s); 8.30 (1H, s); 7.83 (1H, s); 7.67-7.18 (10H, m); 4.10 (4H, br); 3.08 (2H, t, J=7.1 Hz); 1.80-1.20 (16 H, m); 0.89 (3H, t, J=6.6 Hz). High-resolution mass spectrum: calc. for C32H39N7S 554.3066, obs. 554.3053, diff. 2.3 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:23](=[O:24])[N:22]([CH3:25])[C:14]3[N:15]=[C:16](S(C)=O)[N:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:16]2[N:17]=[CH:18][C:13]3[CH:12]=[C:11]([S:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[C:23](=[O:24])[N:22]([CH3:25])[C:14]=3[N:15]=2)=[CH:29][CH:28]=1
Reactant: Cn1c(=O)c(S(=O)(=O)c2ccc(Cl)cc2)cc2cnc(S(C)=O)nc21
Reactant: Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(S(=O)(=O)c2ccc(Cl)cc2)cc2cnc(Nc3ccc(Cl)cc3)nc21
Temperature: 25 °C

Procedure:
A mixture of 6-(4-chlorophenylsulfonyl)-8-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1 eq) and 4-chloroaniline (1.5 eq) in toluene was refluxed overnight. After completion of the reaction (monitored by TLC) the reaction mixture was cooled to ambient temperature. The solid separated, was filtered, washed with hexane, and dried to afford the desired compound.
Reaction SMILES: [F:1][C:2]([F:17])([C:13]([F:16])([F:15])[F:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[S:5](F)(=[O:7])=[O:6].C(N(C(C)C)C(C)C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[OH:46])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>CN(C1C=CN=CC=1)C.ClCCCl>[C:27]([O:31][C:32]([N:34]1[CH2:35][CH2:36][CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][S:5]([C:4]([F:9])([F:10])[C:3]([F:11])([F:12])[C:2]([F:1])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:7])=[O:6])[CH2:38][CH2:39]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
Nonafluoro-butane-1-sulfonyl fluoride (2.71 mL; 15.1 mmol) was added to a mixture of ethyl-diisopropyl-amine (2.87 mL; 16.5 mmol), 4-(N,N-dimethylamino)-pyridine (25 mg) and 4-(2-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (3.81 g; 13.7 mmol) in 50 ml 1,2-dichloro-ethane at 0° C. under argon. The reaction mixture was allowed to warm to room temperature and stirred 16 hours. The reaction mixture was extracted with water (100 mL) and brine (100 mL). The combined aqueous phases were extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (100 mL), dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; ethyl acetate/heptane) to give 4.34 g 4-[2-(nonafluorobutane-1-sulfonyloxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (7.76 mmol; 57%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C:19]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:18][CH:17]([CH2:25][C:26]([OH:28])=[O:27])[C:16]1=[O:29])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)([CH3:32])[CH3:31].Cl>C(Cl)Cl.C(N(CC)CC)C>[CH2:8]([N:15]1[C:19]2([CH2:20][CH2:21][N:22]([C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([CH:30]([CH3:31])[CH3:32])=[CH:34][CH:35]=3)[CH2:23][CH2:24]2)[S:18][CH:17]([CH2:25][C:26]([OH:28])=[O:27])[C:16]1=[O:29])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CC1SC2(CCNCC2)N(Cc2ccccc2)C1=O
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(C(=O)N2CCC3(CC2)SC(CC(=O)O)C(=O)N3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 5 ml of methylene chloride was suspended 0.25 g of 4-isopropylbenzoic acid. Then, at ambient temperature, 0.12 ml of thionyl chloride and 0.03 ml of N,N-dimethylformamide were added. After stirring the mixture at the same temperature as above for one hour, the solvent was distilled off under reduced pressure, and an azeotropic distillation treatment using toluene was carried out to obtain 0.25 g of 4-isopropylbenzoic acid chloride. To a suspension of 0.50 g of trifluoroacetic acid salt of 2-(4-benzyl-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid in 5 ml methylene chloride were successively added dropwise at 0-5° C. 0.64 ml of triethylamine and a solution of 0.25 g of 4-isopropylbenzoic acid chloride in 5 ml methylene chloride. The resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluents: toluene:ethyl acetate=1:1, followed by chloroform] gave 0.30 g of 2-[4-benzyl-8-(4-isopropylbenzoyl)-3-oxo-1-thia-4,8-diazaspiro[4.5]-decan-2-yl]-acetic acid as a light yellow solid product.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:17][C:18]1[C:21](=[O:22])[C:20](=[O:23])[C:19]=1[NH:24][CH2:25][CH2:26][CH2:27]Cl>CN(C)C=O>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:27][CH2:26][CH2:25][NH:24][C:19]2[C:20](=[O:23])[C:21](=[O:22])[C:18]=2[NH2:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: Nc1c(NCCCCl)c(=O)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1c(NCCCOc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A mixture of sodium hydride (0.16 g; 50% dispersion in oil) in dimethylformamide (20 ml) was cooled to 0° C. To this was added dropwise 3-(piperidinomethyl)phenol (0.6 g) in dimethylformamide (10 ml) and the mixture was allowed to warm to room temperature and stirred for 150 minutes. 1-Amino-2-(3-chloropropylamino)cyclobut-1-ene-3,4-dione (0.6 g) in dimethylformamide (30 ml) was added dropwise and the reaction mixture stirred for 20 hours. On examination by thin layer chromatography it was found that the reaction had not gone to completion. Sodium hydride (0.16 g; 50% dispersion in oil) was added, the reaction mixture stirred for 3 hours at room temperature, then stirred for 3 hours at 65° C. and cooled. The reaction mixture was evaporated under reduced pressure, the residue was treated with dilute sodium hydroxide and extracted into chloroform/methanol (9:1). The chloroform/methanol extracts were combined, dried oer magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound; δppm 1.45 (6H, m), 2.00 (2H, m), 2.40 (4H, m), 3.43 (2H, s), 3.65 (2H, m), 4.03 (2H, t), 6.85 (3H, m), 7.23 (1H, t), 7.50 (broad m) (spectrum consistent with an authentic sample).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([Cl:15])[CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](OB(O)O)=[CH:19][CH:18]=1>>[Cl:15][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: CCOC(=O)COc1ccc(Br)cc1Cl
Product: CCOC(=O)COc1ccc(-c2ccc(F)cc2)cc1Cl

Procedure:
Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and 4-fluoro-phenylboric acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:33][C:32]5[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1cccc(C[Zn+])c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3cccc(F)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-fluoro-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 4): tR=1.22 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: FC(C1NC(=O)C2N=CC=CC=2N=1)(F)F.O=P(Cl)(Cl)[Cl:18].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[CH:25][C:26]2[N:27]=[CH:28][NH:29][C:30](=O)[C:31]=2[N:32]=1>>[Cl:18][C:30]1[C:31]2[N:32]=[C:23]([C:22]([F:35])([F:34])[F:21])[CH:24]=[CH:25][C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(C(F)(F)F)nc12
Agent: O=c1[nH]c(C(F)(F)F)nc2cccnc12
Product: FC(F)(F)c1ccc2ncnc(Cl)c2n1
Temperature: 25 °C

Procedure:
The title compound was prepared from trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one using the procedure described in Example 599, Step 2. A POCl3 (9.3 ml) suspension of 6-Trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one (1.0 g, 4.7 mmol) was heated at reflux for 4 hours, over which time the amber suspension became a clear, deep blue solution. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue concentrated from dichloromethane 3× to remove residual POCl3. The residue was partitioned between 1:1 EtOAc and saturated sodium bicarbonate (28 ml). The mixture was stirred until visible gas evolution ceased. The suspension was filtered through a plug of celite. The layers of the filtrate were separated, and the organic phase was washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried with magnesium sulfate and concentrated under reduced pressure to yield the semi-pure product as a purple solid. No further purification was carried out. The crude product was greater than 90% pure (as determined by analytical HPLC). MS: ES+ 234.11 (M+H, 100%
Reaction SMILES: [C:1](=[O:4])([OH:3])N.[NH:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8]>C1C=CC=CC=1>[C:1](=[O:4])=[O:3].[NH:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8]
Reactant: NC(=O)O
Solvent: OCCNCCO
Solvent: c1ccccc1
Product: O=C=O

Procedure:
In this example, it was asserted that a white, pulverulent diethanolamine carbamate was obtained by the introduction of carbon dioxide into a solution of diethanolamine in benzene.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.CS(Cl)(=O)=O.[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[K+]>C(Cl)Cl.CN(C=O)C.C(N(CC)CC)C>[C:30]1([S:36][CH2:2][CH2:3][N:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]2=3)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Reactant: Sc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCSc3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
tert-Butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate, (0.0488 g, 0.148 mmol) was dissolved in CH2Cl2 (5 mL) and stirred at rt. Triethylamine (5 mL) was added, followed by methanesulfonyl chloride (0.017 mL, 0.221 mmol, 1.50 equiv.). The reaction mixture was stirred for 2 h, and additional methanesulfonyl chloride (0.015 mL) was added. After 30 min, a mixture of thiophenol (0.065 mL, 0.592 mmol, 4.0 equiv.) and KOH (12 equiv.) in DMF (5 mL) was added, and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl, then the resulting mixture was extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by PTLC (1 mm×20 cm×20 cm SiO2 plates, developed with 1:4 EtOAc:hexane) to give tert-butyl 6-[2-(phenylsulfanyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.017 g) in 28% yield as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.52, 2.92, 2.99, 3.17, 3.66-3.73, 4.28, 7.10-7.20, 7.25-7.41, 7.48; MS (ESI+) for C25H30N2O2S m/z 423 (M+H)+.