Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([S:15][C:16]2[N:20]([CH3:21])[C:19]([CH2:22][C:23](OC)=[O:24])=[N:18][C:17]=2[CH:27]([CH3:29])[CH3:28])[CH:11]=[C:12]([Cl:14])[CH:13]=1>C(OCC)C>[Cl:14][C:12]1[CH:11]=[C:10]([S:15][C:16]2[N:20]([CH3:21])[C:19]([CH2:22][CH2:23][OH:24])=[N:18][C:17]=2[CH:27]([CH3:29])[CH3:28])[CH:9]=[C:8]([Cl:7])[CH:13]=1
Reactant: COC(=O)Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 81.9 %

Procedure:
To a suspension of 0.08 g (2.1 mmol)of lithium aluminium hydride in dry diethyl ether was added dropwise in nitrogen gas a solution of 0.766 g (2.05 mmol)of methyl [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]acetate (33)in diethyl ether (10 ml)under ice-cooling over 10 minutes with stirring. The reaction mixture was stirred at the same temperature for 0.5 hours and at room temperature for 1 hour, and then, there was added ice-water. The ether layer was separated by decantation, and the aqueous layer was extracted with diethyl ether. The ether extracts were combined, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from isopropyl ether, and filtered to give 0.58 g of 2-[5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]ethanol (Compound I-81a)(yield 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([Br:24])[C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2nc(-c3cccc(OC)c3)sc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2nc(-c3cccc(OC)c3)sc2c1O
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A mixture of 7-hydroxy-2-(3-methoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (643 mg, 1.95 mmole), N-bromosuccinimide (364 mg, 2.04 mmole) and benzoyl peroxide (23 mg, 9.74 mmole) in carbon tetrachloride (9.5 ml) was refluxed for 5 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (338 mg). MS: (+) m/z 409.11, 411.11 (M+1, 79Br/81Br).
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12]C)=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>CO.O>[O:1]1[C:9]2[CH:8]=[C:7]([C:10]([OH:12])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cc2occc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2occc2cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 9.1 %

Procedure:
Methyl furo[3,2-c]pyridine-6-carboxylate (1.55 g, 8.74 mmol) is dissolved in MeOH (30 mL) and H2O (15 mL), treated with 3 N NaOH (6.4 mL) and stirred at rt for 7 h. The mixture is concentrated to dryness, dissolved in H2O (10 mL) and acidified to pH 2 with concentrated HCl. The solution is concentrated to dryness, suspended in a smaller amount of water (7 mL) and the resulting solid collected via filtration (lot A). The filtrate is concentrated, triturated with water (3 mL) and the resulting solid collected via filtration (lot B). The filtrate from lot B is concentrated and carried on without further purification as an acid/salt mixture (lot C). Both lots A and B are dried in a vacuum oven at 50° C. for 18 h to afford 690 mg (48%) for lot A, 591 mg (42%) for lot B and 130 mg (10%) of furo[3,2-c]pyridine-6-carboxylic acid as yellow solids. MS (CI) m/z: 164 (M+H+).
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[C:36]([OH:38])=[O:37])([OH:3])=[O:2]>C(O)C.[Pd]>[C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[C:36]([OH:38])=[O:37])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1/C=C/C(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CCO
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1CCC(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of (1RS,2SR,3SR)-3-[2-[(E)-2-carboxy-ethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxy-phenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (43 mg, 0.08 mmol) in ethanol (5 mL) was added 10% palladium on activated carbon (40 mg). The resulting suspension was stirred overnight under an atmosphere of hydrogen then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford the title compound (35 mg, 82%) as a white solid.
Reaction SMILES: [C:1](=[O:19])(SCC)[O:2][CH2:3][O:4][C:5](=[O:15])[CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].S(Cl)([Cl:23])(=O)=O>>[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:7][CH2:6][C:5]([O:4][CH2:3][O:2][C:1]([Cl:23])=[O:19])=[O:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCSC(=O)OCOC(=O)CCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)CCC(=O)OCOC(=O)Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of carbonothioate 2 (1.06 g, 3.63 mmol) in ice-cold CH2Cl2 (18 mL) was added sulfuryl chloride (441 μL, 5.44 mmol) and the mixture was stirred at 0° C. for 2 h 10 min, after which an additional amount of sulfuryl chloride (147 μL, 1.82 mmol) was added. The mixture was concentrated to dryness, providing chloroformate 3 as a colorless oil (1.13 g, >quant.) which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.57-2.60 (m, 2H), 2.66-2.70 (m, 2H), 5.84 (s, 2H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[N:9]=[N:10][CH:11]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[I:20]N1C(C)(C)C(=O)N(I)C1=O>>[I:20][C:15]1[CH:14]=[C:13]([C:12]2[C:7]3[N:6]=[CH:5][N:4]([CH:1]4[CH2:3][CH2:2]4)[C:8]=3[N:9]=[N:10][CH:11]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: Fc1ccc(-c2cnnc3c2ncn3C2CC2)cc1
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Product: Fc1ccc(-c2cnnc3c2ncn3C2CC2)cc1I
Yield: 79 %

Procedure:
Prepared by a Method analogous to that as described above for Preparation 87 using 7-cyclopropyl-4-(4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 93) and 1,3-diiodo-5,5-dimethylhydantoin to afford the title compound in 79% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[NH:27][C:28](=[O:31])[CH:29]=[CH2:30].NC1C=C2C(=CC=1NC(=O)C=C)N=CC(C#N)=C2NC1C=C(OC)C(OC)=C(OC)C=1.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>CN(C)C=O>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[NH:27][C:28](=[O:31])[CH2:29][CH2:30][N:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1
Reactant: C=CC(=O)Nc1cc2c(Nc3cc(OC)c(OC)c(OC)c3)c(C#N)cnc2cc1N
Reactant: C1COCCN1
Agent: C=CC(=O)Nc1cc2ncc(C#N)c(Nc3cc(OC)c(OC)c(OC)c3)c2cc1N
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(N)c(NC(=O)CCN4CCOCC4)cc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of 0.025 g (0.06 mmol) of N-[7-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-6-quinolinyl]acrylamide and N-[6-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]acrylamide and 0.05 mL (6.0 mmol) of morpholine in 0.2 mL of N,N-dimethylformamide is stirred at room temperature overnight and the solvent is evaporated to dryness to yield an oil. The oil is triturated with diethyl ether several times and dried to yield 0.03 g of N-[7-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-6-quinolinyl]-3-(4-morpholinyl)propanamide and N-[6-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]-3-(4-morpholinyl)propanamide as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:17][N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nn1cccc1
Product: Oc1cccc(Nc2nc(Nn3cccc3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with 1-aminopyrrole to provide 5-fluoro-N4-(3-hydroxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.95 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), 7.99 (d, 1H, J=3.5 Hz), 7.22 (d, 1H, J=8.2 Hz), 6.94 (br s, 1H), 6.89 (t, 1H, J=8.2 Hz), 6.70 (dd, 2H, J=2.3 and 4.7 Hz), 6.38 (d, 1H, J=8.2 Hz), 5.99 (t, 2H, J=2.3 and 4.7 Hz). LCMS: ret. time: 18.23 min.; purity: 94%; MS (m/e): 286 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.[Cl:16][C:17]1[C:22]([CH3:23])=[C:21]([CH2:24][F:25])[N:20]=[CH:19][N:18]=1.C(N(CC)CC)C.Cl.C(OCC)C>CN(C)C=O.CO.O>[ClH:16].[F:25][CH2:24][C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[C:22]=1[CH3:23]
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: Cc1c(Cl)ncnc1CF
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: Cc1c(CF)ncnc1NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Temperature: 100 °C
Reaction time: 28 h
Yield: 2.9 %

Procedure:
A solution of 1-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 300 mg, 1.394 mmol) in dry N,N-dimethylformamide (DMF) (15.000 mL) was treated with 4-chloro-6-(fluoromethyl)-5-methylpyrimidine (Intermediate 51, 336 mg, 2.091 mmol) and triethylamine (0.389 mL, 2.79 mmol). The reaction mixture was heated at 100° C. and stirred for 28 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic extract was then dried under magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified on SP4 column chromatography (25+M) eluting with 0-100% isohexane-ethyl acetate. Product containing fractions were combined and evaporated under reduced pressure. The white residue was then dissolved in 1:1 ethyl acetate:methanol (2 mL) and 1M HCl in diethylether (0.05 mL, 0.543 mmol) was added. The mixture was then evaporated to dryness to give the title compound as a white solid (15 mg);
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.Cl.[NH2:13][CH:14]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[C:4]1(=[O:6])[N:13]([CH:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]1=2
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)C2=C(CCCC2)C1=O
Yield: 23.6 %

Procedure:
To a stirred suspension of 3,4,5,6-tetrahydrophthalic anhydride (0.38 grams, 2.5 mmol) and methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (0.69 grams, 2.5 mmol) in acetic acid (10 mL) was added sodium acetate (0.21 grams, 2.5 mmol). The suspension was refluxed under nitrogen overnight. The acetic acid was removed in vacuo to afford an orange oil which was taken up in water (5 mL) and the pH was adjusted to 7 using a saturated solution of sodium bicarbonate. The resulting mixture was extracted with methylene chloride (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 0.62 grams of crude product as a yellow oil. The crude product was purified by flash chromatography (silica gel, 35% ethyl acetate/hexane) and the resulting solid was dried in vacuo (60° C., <1 mm) to afford 0.22 g (23%) of product as a pale yellow solid: 1H NMR (CDCl3) δ 7.09-6.99(m, 2H), 6.84-6.75(m, 1H), 5.60-5.48(m, 1H), 3.87(s, 3H), 3.85(s, 3H), 3.71-3.55(m, 1H), 3.65(s, 3H), 3.23-3.06(m, 1H), 2.38-2.21(m,4H), 1.85-1.64(m, 4H); 13C NMR (CDCl3) δ 171.1, 170.8, 148.9, 148.7, 120.1, 111.2, 110.9, 55.9, 55.8, 50.4, 36.1, 21.2, 19.9. Anal. Calcd for C20H23NO6. Theoretical: C, 64.33; H, 6.21; N, 3.75. Found: C, 64.25; H, 6.10; N, 3.70.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[N:24][S@@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH3:23])=[C:18]([CH3:31])[CH:17]=1.O>O1CCCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][S@@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH3:23])=[C:18]([CH3:31])[CH:17]=1
Reactant: CC(=N[S@](=O)C(C)(C)C)c1ccc(Br)cc1C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1[C@H](C)N[S@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium tri-sec-butylborohydride (1 mol/L in tetrahydrofuran, 59.2 mL) was added to a solution of (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methyl-phenyl)-ethylidene]-amide (6.24 g) in tetrahydrofuran (50 mL) chilled in an ice bath. The solution was stirred for 2 h while warming to room temperature in the cooling bath. The solution was then cooled again in an ice bath prior to the careful addition of water. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with water, saturated aqueous NaHCO3 solution, and brine. After drying (MgSO4) and evaporating the solvent, the title compound was obtained that was directly submitted to the next reaction step. Yield: 8.85 g (ca. 75% pure); Mass spectrum (ESI−): m/z=318/320 (Br) [M+H]+.
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[O:15][C:14]([CH3:38])([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)[CH2:13][C:12]2=[O:39])(=[O:7])[CH3:6].Cl>C1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[O:15][C:14]([CH3:38])([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)[CH2:13][CH:12]2[OH:39])(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1 g of sodium borohydride was added, whilst ice-cooling, to a mixture of 100 ml of methanol and 10 ml of benzene containing 13 g of 6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman-4-one (prepared as described in Preparation 19), and the mixture was stirred for 30 minutes whilst ice-cooling. The reaction mixture was then poured into ice-water, neutralized with 10% w/v aqueous hydrochloric acid and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography, eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: ClC1C(NC2C=C(C)NN=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11]C[CH:9]2[C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23]C=CN=3)[CH:15]=2)=[N:6]C=1>CO>[CH:19]1([C:16]2[CH:15]=[C:14]([CH:9]3[CH2:11][CH2:12][CH2:13][N:8]3[C:5](=[NH:4])[NH2:6])[O:18][N:17]=2)[CH2:24][CH2:23]1
Reactant: Cc1cc(Nc2nc(N3CCCCC3c3cc(-c4ccccn4)no3)ncc2Cl)n[nH]1
Solvent: CO
Product: N=C(N)N1CCCC1c1cc(C2CC2)no1
Temperature: 60 °C

Procedure:
A mixture of 2-(3-cyclopropylisoxazol-5-yl)pyrrolidine (Method 14) (2.05 g, 11.5 mmol) and formamidinesulphonic acid (1.425 g, 11.5 mmol) in dry methanol (30 ml) was heated at 60° C. for 18 hours. The solvent was removed by evaporation and the residue dissolved in water. The aqueous solution was washed with water and then the water removed by evaporation. The residue was triturated with ether/DCM, the solid product was collected and dried under vacuum at 50° C. for 18 hours to give the title compound monosulphate salt (1.839 mg, 41%); m/z 221 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][CH2:17][C:18](Cl)=O>>[Cl:16][CH2:17][C:18]1[N:12]2[N:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:9]=[CH:10][C:11]2=[N:14][N:15]=1
Reactant: O=C(Cl)CCl
Reactant: NNc1ccc(-c2cccc(Cl)c2)nn1
Product: ClCc1nnc2ccc(-c3cccc(Cl)c3)nn12

Procedure:
As for Example 2, 6-(3-chlorophenyl)-3-hydrazinopyridazine is reacted with chloroacetyl chloride to give the product of the Example.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=1>>[CH3:14][C:15]([CH3:19])([CH3:18])[CH:16]=[CH:17][C@@H:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:33])=[CH:26][CH:27]=1)[OH:32]
Reactant: Cc1ccc(C=O)cc1
Reactant: C#CC(C)(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: Cc1ccc([C@@H](O)C=CC(C)(C)C)cc1
Yield: 86 %

Procedure:
The product was prepared by General procedure S using 98 mg (0.55 mmol) Cy2BH, 68 μL (0.55 mmol) 3,3-dimethyl-1-butyne, 0.55 mL (1.1 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, and 59 μL (0.50 mmol) p-tolualdehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a white solid in 86% yield (88 mg, 0.43 mmol). m.p.: 38-40° C.; [α]D20=+52.7 (c=0.97, CHCl3, 95% ee); 1H NMR (CDCl3, 500 MHz): δ 0.95 (s, 9H), 1.83 (br s, 1H), 2.26 (s, 3H), 5.03 (d, 1H, J=6.7 Hz), 5.47 (dd, 1H, J=15.6, 6.8 Hz), 5.70 (d, 1H, J=15.6 Hz), 7.07 (d, 2H, J=7.7 Hz), and 7.17 (d, 2H, J=7.9 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 21.1, 29.4, 32.8, 75.2, 126.1, 127.2, 128.1, 137.1, 140.6, and 143.2 ppm; IR (film): 3346, 3023, 2959, 2865, 2361, 2334, 1655, 1613, 1513, 1478, 1461, 1416, 1388, 1362, and 1268 cm−1; HRMS-CI m/z 204.1509 [M+; calcd for C14H20O: 204.1514].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[C:29]2[N:28]=[C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]3)[CH:26]=[N:25][C:24]=2[C:23]([C:39](O)=[O:40])=[CH:22][CH:21]=1>C(Cl)Cl.CO>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39]([C:23]2[C:24]3[N:25]=[CH:26][C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]4)=[N:28][C:29]=3[C:20]([C:10]3[C:9]([Cl:8])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=3[Cl:19])=[CH:21][CH:22]=2)=[O:40])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: CCN1CCN(Cc2cnc3c(C(=O)O)ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c3n2)CC1
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2cnc3c(C(=O)Nc4cccnc4)ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c3n2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-aminopyridine, 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylic acid (Step 83.1) and stirring the reaction mixture for 2 days at rt. Title compound: ESI-MS: 581.0/583.2 [M+H]+; tR=3.04 min (System 1); TLC: Rf=0.33 (DCM/MeOH, 9:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(F)ccc2Nc2ccccc21
Reactant: CN(C)CCN
Product: CN(C)CCNC1=Nc2cc(F)ccc2Nc2ccccc21
Yield: 36.9 %

Procedure:
8-Fluoro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (160FE15C) (23 mg, 0.1 mmol) and N,N-dimethylethylenediamine (88 mg, 1.0 mmol) were reacted according to GP4 to give 11 mg of the title compound (160FE20D). MS (ESI) 299 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([NH2:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].Cl.[O-:25][C:26]#[N:27].[K+]>C(O)C.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([NH:20][C:26]([NH2:27])=[O:25])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: N#C[O-]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3NC(N)=O
Yield: 57.1 %

Procedure:
To a solution of 4-amino-1,8-diethyl-1,3,4,9-tetrahydro[3,4-b]indole-1-acetic acid methyl ester 12 (prepared in Example 1) (1.10 g, 3.48 mmol) in ethanol (20 mL), stirred at room temperature under nitrogen, was added aqueous 1N HCl (6.96 mL) followed by potassium cyanate (0.565 g, 6.96 mmol) dissolved in a little water. After 2 hours the ethanol was removed in vacuo and the residue was extracted with ethyl acetate. Drying (MgSO4) and flash chromatography (1% MeOH in EtOAc eluent) afforded the product (0.714 g, 75%) as a mixture of diastereomers which were separated by reverse phase chromatography (C18 silica gel; 30% acetonitrile in water). The less polar Isomer A (190 mg) had m.p. 179.5°-180.5° C. (methylene chloride-petroleum ether).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]1.CN1CCOCC1>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: CN1CCN(CCO)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
4-Nitrophenyl chloroformate (9.85 g, 49 mmol) was dissolved in DCM (200 mL), and cooled to 0° C. 2-(4-methylpiperazin-1-yl)ethanol (7.2 g, 50 mmol) and NMM (6 mL) were added, and the reaction mixture was allowed to warm gradually to room temperature over 16 hours. The reaction mixture was washed with 1M aq Na2CO3 solution until the yellow colour extracted into the aqueous layer had disappeared. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 2-(4-methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (10.7 g, 71%) as a yellow oil which solidified on standing.