Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C@@H:9]([N:16](CS)[C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]3[N:31]4[CH2:32][CH2:33][NH:34][CH2:35][C:30]4=[N:29][N:28]=3)(=[O:25])=[O:24])=[CH:19][C:18]=2[S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])C2C=CC=CC=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([N:34]2[CH2:33][CH2:32][N:31]3[C:27]([NH:26][S:23]([C:20]4[CH:21]=[CH:22][C:17]([NH:16][C@@H:9]([CH2:39][S:36][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=5)[CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[C:18]([S:36]([C:39]([F:40])([F:41])[F:42])(=[O:38])=[O:37])[CH:19]=4)(=[O:25])=[O:24])=[N:28][N:29]=[C:30]3[CH2:35]2)[CH2:54][CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: O=S(=O)(Nc1nnc2n1CCNC2)c1ccc(N(CS)[C@H](CCN2CCOCC2)c2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCn3c(nnc3NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)C2)CC1
Reaction time: 0.17 h
Yield: 204.5 %

Procedure:
To a vial containing 4-((R)-3-morpholin-4-yl-1-phenyl-sulfanylmethyl-propylamino)-N-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-trifluoromethanesulfonyl-benzenesulfonamide (50 mg, 0.074 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (14.74 mg, 0.074 mmol) was added methanol (2 mL) under nitrogen. The reaction mixture was stirred in an ice bath for 10 minutes, and then acetic acid (0.424 μL, 7.40 μmol) was added. The reaction mixture was stirred for another 30 minutes. Sodium cyanoborohydride (41.85 mg, 0.666 mmol) was then added, and the reaction was stirred at ambient temperature for 72 hours. The reaction mixture was concentrated, filtered and purified via flash chromatography on silica gel (10-50% 7N NH3 in methanol in CH2Cl2) to afford 4-{3-[4-((R)-3-Morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonylamino]-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl}-piperidine-1-carboxylic acid tert-butyl ester (65 mg, 100% yield). MS [m/z; (M+1)+]: 859.7
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2([CH3:10])[C:7]([CH2:9][CH:3]1[CH2:4][CH2:5]2)=[O:8].C([N-]C(C)C)(C)C.[Li+].[C:20](=[O:22])=[O:21].C(OCC)C>C1(C)C=CC=CC=1>[CH3:10][C@@:6]12[C:2]([CH3:11])([CH3:1])[C@@H:3]([CH2:4][CH2:5]1)[CH:9]([C:20]([OH:22])=[O:21])[C:7]2=[O:8]
Reactant: CC12CCC(CC1=O)C2(C)C
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Following the procedure of W. W. Shumway et al. J. Org. Chem. 2001, 66, 5832-5839, L-(−)-camphor (15 g, 98.5 mmol) was dissolved in toluene (62 mL), cooled to −78 degrees, and lithium diisopropylamide (1.8 M solution in heptane/tetrahydrofuran/ethylbenzene; 98.5 mL, 197 mmol, 2 equiv.) was added via an addition funnel over 15 min. The resulting solution was stirred at −78 degrees for 30 min, warmed to room temperature, and carefully poured over an excess of pulverized dry ice (300 g). Toluene (30 mL) was added and the solution was allowed to warm to room temperature. Diethyl ether (100 mL) was added and the solution was extracted with water (3×150 mL). The organic layer was discarded. The aqueous layer was acidified with 2M HCl to pH 1, salted with solid sodium chloride, and extracted with ether (3×150 mL). The combined organic extracts were dried (sodium sulfate), filtered, and evaporated to give (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid (16.0 g, 83%) as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=2)[NH2:43])[CH2:36][CH2:35]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:43][C:42]5[CH:44]=[CH:45][CH:46]=[C:40]([N:37]6[CH2:36][CH2:35][N:34]([CH3:33])[CH2:39][CH2:38]6)[CH:41]=5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)Nc2cccc(N3CCN(C)CC3)c2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid and 3-(4-methylpiperazin-1-yl)aniline with yield 35 mg (28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.72 (m, 6 H) 1.98 (br. s., 2 H) 2.22 (s, 2 H) 2.35-2.50 (m, 4 H) 2.97-3.23 (m, 4 H) 3.98 (s, 3 H) 4.06 (t, J=12 Hz, 2 H) 4.79 (m, 1 H) 6.55-6.79 (m, 1 H) 7.12-7.26 (m, 2 H) 7.40 (s, 1 H) 7.52-7.72 (m, 2 H) 8.03 (s, 1 H) 8.28 (s, 1 H) 8.35 (d, J=8.34 Hz, 1 H) 9.94 (s, 1 H). [M+H] calc'd for C32H38F2N8O3, 621; found 621.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH:32]C(=O)OCC5C=CC=CC=5)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:43][CH3:44])[N:8]=[CH:7][C:6]=2[N:5]([CH3:45])[C:4]1=[O:46])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:32][CH2:31][CH2:30][CH2:29][N:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:9]3[N:8]=[CH:7][C:6]4[N:5]([CH3:45])[C:4](=[O:46])[C@@H:3]([CH2:1][CH3:2])[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]=4[N:10]=3)=[C:18]([O:43][CH3:44])[CH:19]=2)[CH2:24][CH2:25]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(N4CCN(CCCNC(=O)OCc5ccccc5)CC4)cc3OC)nc2N1C(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(N4CCN(CCCN)CC4)cc3OC)nc2N1C(C)C
Temperature: 20 °C
Reaction time: 24 h

Procedure:
33 mg (0.045 mmol) benzyl (3-{4-[4-((R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-3-methoxy-phenyl]-piperazin-1-yl}-propyl)-carbamate are taken up in 5 ml of methanol combined with 4 mg palladium hydroxide and stirred for 24 h at 20° C. and 7 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]3)=[CH:4][C:3]=1[O:22][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Brc1ccccn1
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1Oc1ccccn1
Yield: 24.5 %

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (50.0 mg, 0.16 mmol) was alkylated with 2-bromopyridine (18.6 μL, 30.8 mg, 0.20 mmol) as described in Example 47, except that heating at 150° C. overnight was required, affording 5-[4-fluoro-3-(pyridin-2-yloxy)phenyl]-2-trifluoromethyl[1,8]naphthyridine (15.1 mg, 24%). δH (400 MHz, CDCl3) 7.04-7.09 (2H, m), 7.30-7.35 (1H, m), 7.38-7.43 (2H, m), 7.60 (1H, d, J 4.7), 7.73-7.79 (1H, m), 7.83 (1H, d, J 8.6), 8.17 (1H, dd, J 5.1 and 2.0), 8.64 (1H, d, J 8.6), 9.27 (1H, d, J 4.3). m/z (ES+) 386 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Br:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:12][C:11]1[C:2]([NH:1][C:16]2[C:17]([Cl:21])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cccc(Br)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(Br)c1Nc1nc(Cl)ncc1Cl
Temperature: 85 °C
Yield: 7.3 %

Procedure:
A mixture of 2-amino-3-bromo-N-methyl-benzamide (420 mg), 2,4,5-trichloropyrimidine (540 mg) and K2CO3 (47 mg) in DMF was heated at 85° C. overnight. The reaction mixture was loaded on silica gel, dried in vacuo, and purified by silica gel chromatography to provide 50 mg of 3-bromo-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 8.4 (bs, 1H), 8.3 (s, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.3 (t, 1H), 6.3 (bs, 1H, NH), 3.0 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1.CS([Cl:27])(=O)=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][Cl:27])=[CH:17][CH:16]=1
Reactant: CC(C)Cn1nnc2c(Br)c(-c3ccc(CO)cc3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cn1nnc2c(Br)c(-c3ccc(CCl)cc3)ccc21
Reaction time: 2 h

Procedure:
To a solution of {4-[4-bromo-1-(2-methylpropyl)-1H-benzotriazol-5-yl]phenyl}methanol (234 mg, 0.650 mmol) in dichloromethane (5 ml) at 0° C. was treated with methanesulfonyl chloride (0.056 ml, 0.715 mmol), followed by the dropwise addition of triethylamine (0.181 ml, 1.299 mmol). After 2 hours, the mixture was purified via silica gel chromatography (acetone/dichloromethane gradient), providing the titled compound as white solid. LRMS m/z (M+H) 377.9 and 379.9 found, 378.03 and 380.03 required.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]([O-])=[CH:7][C:6]=2[N:16]=1)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:47]>C(Cl)(Cl)Cl>[NH2:47][C:7]1[C:6]2[N:16]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: [NH4+]
Reactant: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [4-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate in chloroform was added p-toluene sulfonyl chloride (1.2 eq.) followed by aq.ammonium hydroxide solution. The resulting reaction mixture was stirred at room temperature for overnight. Reaction mixture was washed with saturated sodium bicarbonate solution. Organic layer separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield sticky solid, which was then purified using silica gel column chromatography to afford tert-butyl [4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.[NH3:20]>C(O)CO.O>[NH2:20][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC
Reactant: N
Solvent: OCCO
Solvent: O
Product: CCCOc1ccc(-c2ccc(N)nn2)cc1OC
Yield: 81.7 %

Procedure:
10 g (35.9 mmol) of 3-chloro-6-(3-methoxy-4-propoxyphenyl)pyridazine are heated in 50 ml of ethylene glycol which has been saturated with ammonia at 0° C. in an autoclave at 220° C. for 6 hours. After cooling, the reaction mixture is diluted with 500 ml of water, and the precipitate which forms is filtered off with suction. The crude product is dried and then purified by column chromatography on silica gel with chloroform as eluent. 7.6 g (81.7%) of the title compound of m.p. 147° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6][CH:7]=1.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][NH2:34])=[N:31][CH:32]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[CH3:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][NH:34][C:17]([C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][N:12]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:16]=2)=[O:19])=[N:31][CH:32]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc3c2cnn3-c2ccccc2)nc1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc3c2cnn3-c2ccccc2)nc1

Procedure:
4-(5-Methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid was reacted with C-(5-methyl-pyrazin-2-yl)-methylamine in the presence of EDCI, HOBt and NMM using the procedure of step 4 of Example 1 to provide 4-(5-Methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide, MS (M+H)=435.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[OH2:14]>>[O:14]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8]1
Reactant: CC(=O)NC1CCCc2sccc21
Reactant: O
Product: CC(=O)NC1CCC(=O)c2sccc21
Temperature: 60 °C

Procedure:
Into a 100 ml, three necked round bottomed flask is placed 2.0 g of N-(4,5,6,7-tetrahydrobenz[b]-thien-4-yl)acetamide, 15 ml of H2O, and 31.5 ml of a 1.3 M cobaltic acetate solution prepared as in Example II. The mixture is stirred and heated to 60° C. under N2 for 12 hours and is worked up as in Example V. A material weighing 1.9 g and assaying as 76.8% of the product was obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:13][C:9]1[CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Product: Nc1ccc(OC(F)(F)F)cc1Cl

Procedure:
Part A. A solution of 4-trifluoromethoxyaniline (12.0 mL, 88.8 mmol) and N-chlorosuccinimide (13.04 g, 97.7 mmol) in acetonitrile (90 mL) was heated to reflux for 12 h. After cooling, the solution was filtered and evaporated, and the residual material was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to afford the product, 2-chloro-4-trifluoromethoxyaniline, as a liquid. The product was further purified by distillation to afford 18.14 g (85.7 mmol, 97%) pure product, b.p. 50-60° C./5 mm Hg (bulb-to-bulb). 1H NMR (300 MHz, CDCl3): Δ 7.16 (1H, d, J=2.5 Hz), 6.96 (1H, dd, J=8.8, 2.5 Hz), 6.73 (1H, d, J=8.8 Hz), 4.08 (2H, br s). MS (H2O-GC/MS): m/e 214 (27), 213 (17), 212 (100).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:29]1[N:28]=[C:18]([C:17]2[CH:21]=[CH:22][C:14]([N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]3[CH3:7])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[O:20][N:30]=1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3CCCCC3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (106 μL; 1.25 mmol; 3 eq.), Intermediate 24 (120 mg; 0.42 mmol; 1 eq.), Intermediate 1 (69 mg; 0.42 mmol, 1 eq.) and DIEA (93 μL; 1.25 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 80/20) followed by precipitation from n-pentane afforded the title compound as a white solid.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])(O)=[O:2].B.O>C1COCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:8]2[C:9]3[C:14](=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[C:6]([S:5][CH2:4][CH2:1][OH:2])=[C:7]2[CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)C(C)(C)Cc1c(SCC(=O)O)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)Cc1c(SCCO)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the acid from Step 4 (3.8 g, 8.23 mmol) in THF (200 mL) there was added 0.9M borane in THF (25 mL) and the mixture was stirred at r.t. for 1.5 hours. Water (25 mL) was added and the THF removed by evaporation. More H2O was added along with 2N HCl (15 mL) and the mixture was extracted with Et2O 3 times. These extracts were washed with H2O 4 times, dried and evaporated to leave a residue which was chromatographed on silica gel, eluting with a 1:1 mixture of hexane and EtOAc. The title compound was obtained as a thick oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]CC)=[O:20])[CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2cccc(OCc3ccccc3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2cccc(OCc3ccccc3)c2c1

Procedure:
A solution of ethyl 5-benzyloxyquinoline-3-carboxylate (3.07 g, 10 mmol) prepared in stage A and LiOH (0.4 g, 20 mmol) in THF (20 mL)and water (0.5 mL) was refluxed for 2 hours. After cooling, the solvents were evaporated under vacuum. The solid residue was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:21]([C:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([C:5]4[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=4[O:3][CH2:1][CH3:2])[C:12]=3[NH:19][C:18]=2[CH3:20])=[O:22])[CH2:29][CH2:28]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(C)=O)CC3)c(C)[nH]c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f17) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:39]=[C:40]([CH2:48][CH3:49])[C:41]2[O:46][CH2:45][O:44][CH2:43][C:42]=2[CH:47]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:21](=[O:20])[NH:22][C:23]([CH:24]([C:38]2[CH:39]=[C:40]([CH2:48][CH3:49])[C:41]3[O:46][CH2:45][O:44][CH2:43][C:42]=3[CH:47]=2)[NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:30][CH:31]=2)=[N:11]1)=[O:4]
Reactant: COC(=O)c1scnc1NN
Reactant: CCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc2c1OCOC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncsc3C(=O)OC)c(=O)[nH]2)cc2c1OCOC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
After adding 71 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example (162c)) and 300 μl of triethylamine to a solution of 198 mg of [2-(8-ethyl-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (27b)) in 6 ml of THF, the mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The reaction mixture was then concentrated. The residue was dissolved in 6 ml of DMF, and then 0.3 ml of triethylamine was added and the mixture was stirred at 80° C. for 6 hours.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:4]=2[O:3]1.Cl.[OH-].[Na+]>O.C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:4]2[O:3][C:2]([CH3:1])([CH3:15])[CH:7]=[CH:6][C:5]=2[CH:8]=1
Reactant: CC1(C)C=Cc2cc([N+](=O)[O-])ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)C=Cc2cc(N)ccc2O1
Temperature: 60 °C
Reaction time: 0.83 h

Procedure:
2,2-dimethyl 6-nitro 2H-1-benzopyran (3), 40.1 g (185 mmol) was mixed with 120 g of ethanol, 28.0 g of water and 36.1 g of reduced iron, the resulting mixture was heated to 60° C., and a mixed solution of 4.0 g of 35% (w/w) hydrochloric acid, 16.0 g of ethanol and 4.0 g of water was added dropwise thereto over 50 minutes. After stirring at the same temperature for 2 hours, 10.0 g of 15% (w/w) sodium hydroxide aqueous solution was added dropwise thereto, the resulting mixture was filtered through celite, and then the solvent was distilled off. To 112 g of the resulting residue, 160 g of toluene and 68.0 g of 10% (w/w) sodium hydroxide aqueous solution were added, the resulting mixture was shaken, left and separated into phases. The aqueous phase was extracted with 68 g of toluene again. The organic phases were combined and washed with 68 g of 5% (w/w) sodium chloride solution, and the solvent was distilled off to obtain a solution of the intended product, 6-amino 2,2-dimethyl 6-2H-1-benzopyran (4) (68.0 g).