Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[Cl:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(Cl)c(Cl)c4)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3,4-dichlorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′,4′-dichloro-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (4 mg, 3%): m/z (ES+) 434 [MH+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][S:10][C:9]1=[N:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>>[NH2:15][C:14]1[NH:18][N:17]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11][SH:10])[N:13]=1
Reactant: NN
Reactant: N#CN=C1SCCN1Cc1ccccc1
Solvent: O
Product: Nc1nc(N(CCS)Cc2ccccc2)n[nH]1

Procedure:
A mixture of 1.84 g of 3-benzyl-2-cyanoiminothiazolidine and 10 ml of hydrazine monohydrate was heated at reflux under an algon atmosphere for an hour. After the reaction, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 2 g of 5-amino-3-[N-(2-mercaptoethyl)benzylamino]-1,2,4-triazole (Compound 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.I[CH2:25][CH3:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[N:19]([CH2:25][CH3:26])[CH:20]=2)([OH:14])[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:23])[CH:3]=1
Reactant: CCI
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F
Product: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O

Procedure:
In analogy to Example 195, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 205) was alkylated with iodoethane to give the title compound as a light yellow oil. MS (m/e)=438.2 [M+H+].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([OH:12])[CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([Si:22]([CH3:24])([CH3:23])[O:12][C@@H:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:10]=[CH2:11])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@@H](O)CCc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C[C@H](CCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
A stirred solution of allylic alcohol 66 (3.00 g, 18.5 mmol) in CH2Cl2 (53 ml) was cooled to 0° C. Imidazole (2.27 g, 33.3 mmol) was added in one portion followed by t-butylchlorodimethylsilane (3.34 g, 22.2 mmol). The cooling bath was removed and the reaction mixture stirred at r.t. for 16 h before being poured into 10% aq. HCl (100 ml). The mixture was extracted with 40/60 petroleum ether (2×100 ml). The combined organics were washed with saturated NaCl solution (100 ml), dried (MgSO4), filtered, and concentrated to give the crude material. This was purified by column chromatography, eluting with 40/60 petroleum ether, to give the protected alcohol 67 (4.68 g, 92%) as a colourless liquid. The 1H NMR data and optical rotation matched that reported in the literature (Uenishi, J. i. et al., Organic Letters 2011, 13, 2350).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([N:11]=[CH:12][C:13]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([NH:26][C:27]([C:29]4[CH:30]=[CH:31][C:32]5[S:37][CH2:36][C:35](=[O:38])[NH:34][C:33]=5[CH:39]=4)=[O:28])[CH2:22][CH2:21]3)=[N:14]2)=[CH:9][CH:8]=1.CO>ClCCl>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([N:11]=[CH:12][C:13]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([NH:26][C:27]([C:29]4[CH:30]=[CH:31][C:32]5[S:37][CH2:36][C:35](=[O:38])[NH:34][C:33]=5[CH:39]=4)=[O:28])[CH2:22][CH2:21]3)=[N:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1M boron tribromide in dichloromethane (2.93 mL, 2.93 mmol, 8.0 eq) is added at 0° C. to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (190 mg, 0.37 mmol, 1.0 eq) in dichloromethane (2.5 mL). The reaction mixture is stirred at 0° C. for 30 minutes and then at 40° C. for 24 hours. The reaction mixture is cooled down to 0° C. before the addition of methanol (1 mL). Solvents are evaporated and the crude is taken in water (10 mL), the pH is adjusted to 10 by the addition of 1N sodium hydroxide aqueous solution and the resulting aqueous layer is extracted with diclhoromethane (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as a white lyophilizated powder (28 mg, 30% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([CH2:20][CH2:21][F:22])[C:15]([O:17]CC)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([CH2:20][CH2:21][F:22])[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(CCF)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(C(CCF)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from step B (100 mg, 0.3 mmol) in a mixture of THF (1 mL) and methanol (0.3 mL) was added a solution of lithium hydroxide (0.3 mL of a 1 M soln, 0.3 mmol) and the resulting mixture stirred at room temperature for 90 min. 1N HCl (0.3 mL, 0.3 mmol) was added and the mixture evaporated to dryness. The resulting crude product was used immediately without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH:10](O)[CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][C:5]1([CH3:17])[C:6]2[C:14](=[CH:13][C:12]3[CH:11]=[CH:10][CH2:9][C:8]=3[CH:7]=2)[C:2]([CH3:18])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CC(O)C3
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)C=CC3
Yield: 60.9 %

Procedure:
A 1 L round bottom flask fit with a magnetic stirrer, condenser, thermometer, and nitrogen inlet was charged with anhydrous toluene (7 mL, Aldrich), the crude 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indan-2-ol (31.0 g, 0145 mol), pyridine (31.6 mL, 0.39 mol, Aldrich), and p-toluenesulfonyl chloride (30.4 g, 0.16 mol, Aldrich). The mixture was heated to reflux and cooled for GC analysis periodically for a total reflux time of 2 hours. The reaction was then quenched in 5% HCl (250 mL) and extracted into diethyl ether (200 mL). The ether extract was washed with 5% HCl (200 mL), 5% aqueous sodium bicarbonate (until neutral to pH paper), Water (2×200 mL), and dried over anhydrous magnesium chloride. Removal of solvents by rotary evaporation gave 23.0 g of crude product which was purified by chromatography on silica gel (60 g silica gel/hexane eluent) to give 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indene (17.5 g, 92-99+% pure by GC). 1HNMR (CDCl3, 500 MHz) δ7.44 (s, 1H); 7.36 (s, 1H); 6.82 (br d, J=5.5 Hz, 1H); 6.47 (br d, J=5.5 Hz, 1H); 3.51 (s, 2H); 1.70 (s, 4H); 1.32 (s, 12H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([NH2:19])[CH:15]=[CH:14]3)[CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21]>>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([O:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=4)[CH:3]=3)[CH:10]=[CH:11][CH:12]=2)[N:17]=1
Reactant: Nc1ccc2cccc(Oc3cc(Cl)ncn3)c2n1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cc(Oc3cccc4ccc(N)nc34)ncn2)cc1

Procedure:
According to the procedure described for Example 124(b), 8-(6-chloro-pyrimidin-4-yloxy)-quinolin-2-ylamine, (Example 124(a)), (0.20 g, 0.73 mmol) and 4-cyanophenylboronic acid (0.16 g, 1.1 mmol, Aldrich) provided the title compound as a white solid. Mp: 234-2360C. MS (ESI, pos. ion.) nzlz:340 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.C(Cl)(Cl)Cl.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>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(C#C[Si](C)(C)C)c1
Temperature: 50 °C
Yield: 50.3 %

Procedure:
Methyl 4-hydroxy-3-iodobenzoate (5.56 g, 20 mmol) is combined with trimethylsilylacetylene (3.96 mL, 28 mmol), bis(triphenylphosphine)palladium dichloride (414 mg, 0.6 mmol) and cuprous iodide (57 mg, 0.3 mmol) in THF (20 mL)/CHCl3 (40 mL) in a dry flask, under nitrogen. TEA (8.7 mL, 62.3 mmol) is added and the mixture heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5% HCl (2×40 mL), dried (MgSO4) and concentrated to a brown solid. The crude material is adsorbed onto silica gel and chromatographed over 200 g silica gel, eluting with 15% EtOAc/hexane (2 L) followed by 20% EtOAc/hexane (1 L). Fractions are combined and concentrated to afford 2.50 g (50%) of methyl 4-hydroxy-3-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H: 249.0947, found 249.0955 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:10]#N)[NH:8][CH:9]=1)=[O:4].C(O)=[O:13]>[Ni]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[O:13])[NH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c(C#N)c1
Reactant: O=CO
Agent: [Ni]
Product: COC(=O)c1c[nH]c(C=O)c1
Temperature: 0 °C
Yield: 36 %

Procedure:
3.6 g (27 millimoles) of 2-cyanopyrrole-4-carboxylic acid methyl ester, 17 g of Raney nickel, and 450 ml of 75% formic acid are introduced, in a flask, into an oil bath preheated to 120° C. and made to react for one hour. Subsequently, the mixture is poured into 1 liter of ice water and repeatedly extracted with ether. After drying and concentration of the ether phase, 1.4 g (36% of theory) of 2-formylpyrrole-4-carboxylic acid methyl ester is obtained, mp 126° C.
Reaction SMILES: CC(OC([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH2:13][CH2:12]1)=O)CCCCC.C(O[CH2:26][CH3:27])(=O)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH3:17][CH:16]([CH:13]1[CH2:12][NH:11][CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14]1)[CH2:15][CH2:21][CH2:20][CH2:26][CH3:27]
Reactant: CCOC(C)=O
Reactant: CCCCCC(C)OC(=O)N1CCOc2ccccc2C1
Agent: Cl
Product: CCCCCC(C)C1CNCc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
A mixture of tert-butyl 9-bicyclo[2.2.1]hepta-2-yl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (100 mg, 0.292 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (2 ml) was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (24.0 mg, 29.4%) as a solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH3:35])[N:29]=[CH:28][C:27]([C:36]#[N:37])=[C:26]2[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]#[CH:46])[CH:40]=1>C1COCC1.CN1CCCC1=O>[C:36]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]#[CH:46])[CH:40]=1)=[CH:24][C:23]([NH:22][C:7](=[O:8])/[CH:6]=[CH:5]/[CH2:4][N:3]([CH3:10])[CH3:2])=[C:32]([O:33][CH2:34][CH3:35])[CH:31]=2)#[N:37]
Reactant: C#Cc1cccc(Nc2c(C#N)cnc3cc(OCC)c(N)cc23)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2c(C#N)cnc3cc(OCC)c(NC(=O)/C=C/CN(C)C)cc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A solution of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (1.28 g, 7.73 mmol, 2.1 equiv) in THF (18 ml) and a catalytic amount of DMF was cooled to 5° C. while oxalyl chloride (0.67 ml, 0.007 mol, 1.9 equiv) was added slowly. The reaction mixture was then warmed to room temperature and stirred for 3 hours. A solution of 6-amino-7-ethoxy-4-(3-ethynylphenylamino)quinoline-3-carbonitrile (1.2 g, 3.66 mmol, 1.00 equiv) in N-methyl-2-pyrrolidinone (15 ml) was added dropwise over 10 minutes. The mixture was stirred for overnight, quenched with water (200 ml). Aqueous sodium hydroxide was added to bring the pH to 11. The mixture was stirred for 1 hour which formed precipitate. The resulting precipitate was filtered and washed with water and the wet solid was dried to give 1.43 g product. MS (ESI) m/z: 563 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:21])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]=1[OH:22].B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:21])[C:8]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]=1[OH:22]
Reactant: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2Cl)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2Cl)cc1

Procedure:
The title compound was prepared by reacting 1,5-dichloro-8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.15 g, 0.445 mmol) with boron tribromide (0.67 mL of 1 N solution, 0.67 mmol) according to method D to yield 0.12 g (83%) of a light yellow solid mp 206-216° C.; 1H NMR (DMSO-d6): δ 6.88 (2H, d, J=8.55 Hz), 7.34-7.39 (3H, m), 7.51 (1H, d, J=9.34 Hz), 8.21 (1H, dd, J=1.66 Hz, J=9.34 Hz), 9.74 (1H, bs), 10.99 (1H, bs); MS (ESI) m/z321/323/326 (M−H)−.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Br:10])[CH:9]=1.[CH3:12][O:13][CH2:14]Cl>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([O:11][CH2:12][O:13][CH3:14])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(Br)cc(Br)c1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
A flask was charged with sodium hydride (953 mg, 23.8 mmol, 60% in oil), in dry DMF (30 ml) and cooled to 0° C. (ice bath) under nitrogen atmosphere. 3,5-Dibromophenol (5 g, 19.9 mmol) was added in 4 equal portions over 10 minutes. After complete addition the cooling bath was removed and the mixture allowed to warm to ambient temperature over 20 minutes. Chloromethyl methyl ether (1.8 ml, 21.8 mmol) was added slowly, via syringe over about 5 minutes. The mixture was stirred over night. The material was quenched via the addition of saturated aqueous NH4Cl (20 ml) and all volatiles were stripped (rotovap/mechanical pump). The remainder was taken up in water (80 ml) and ethyl acetate (80 ml) and the material shaken in a separtatory funnel. The ethyl acetate phase was collected and washed with an equal volume of brine solution. The aqueous phases were back extracted with ethyl acetate (2×50 ml), the organics combined, dried (MgSO4), filtered and stripped to provide a crude oil. The oil was purified by silica gel chromatography using 4%-6% EtOAc in hexanes as eluant to provide 5.74 g of 1,3-dibromo-5-methoxymethoxy-benzene as a light yellow oil.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[C:8]([C:19]2[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=2[F:27])=[N:7][CH:6]=1)=[O:4].CO>O>[OH:4][CH2:3][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[C:8]([C:19]2[C:20]([F:27])=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[N:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(C=O)cnc(-c3c(F)cc(F)cc3F)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(CO)cnc(-c3c(F)cc(F)cc3F)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
Sodium borohydride (17 mg) was added to a mixture of methyl 4-formyl-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (150 mg) and methanol (10 mL) under ice-cooling, followed by stirring at room temperature for 10 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried, and then concentrated under reduced pressure to obtain methyl 4-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (140 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:21]([CH3:23])[CH3:22])[CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C.[F:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[C:62]([N:70]3[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]3)=[C:63]3[CH:69]=[CH:68][NH:67][C:64]3=[N:65][CH:66]=2)=[CH:57][CH:56]=1>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:10]([C:11]([N:73]2[CH2:74][CH2:75][N:70]([C:62]3[C:61]([C:58]4[CH:59]=[CH:60][C:55]([F:54])=[CH:56][CH:57]=4)=[CH:66][N:65]=[C:64]4[NH:67][CH:68]=[CH:69][C:63]=34)[CH2:71][CH2:72]2)=[O:12])[CH2:9][N:8]([CH:21]([CH3:23])[CH3:22])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:15][CH:16]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: Fc1ccc(-c2cnc3[nH]ccc3c2N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccc(F)cc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
(S)-3-(tert-Butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (87 mg, 0.25 mmol, see Example H), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (65 mg, 0.34 mmol), HOBt-H2O (52 mg, 0.34 mmol) and triethylamine (51 mg, 0.51 mmol) were added to 5-(4-fluorophenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.17 mmol) in DCM (10 mL). The reaction was stirred for 18 hours. The reaction was then diluted with DCM (50 mL) and washed with 1N HCl, 10% K2CO3 and brine. After drying with MgSO4 and concentration, the resulting residue was purified by chromatography (SP4, 12+M, water/ACN 80/20→0/100, 20CV) to yield (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (42 mg, 40% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.C[OH:14]>[Ni]>[NH2:10][C:5]1[C:6]([C:8]([NH2:9])=[O:14])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Ni]
Product: NC(=O)c1nc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
to a suspension of 6-chloro-3-nitro-pyridine-2-carbonitrile (11.01 g, 60 mmol) in methanol (120 ml), was added Raney-Nickel (3 g, washed with methanol to remove water) and the mixture was shaken under a H2-atmosphere at room temperature for 4 hours. The catalyst was removed by filtration, washed with methanol (500 ml). Both filtrates were combined and then evaporated to dryness. The residue was dissolved in dichloromethane and the solution was filtered through a short and wide column with silica gel (100 g). The column was additionally washed with CH2Cl2/MeOH (200 ml, 4:1). The filtrate and washings were combined and evaporated to small volume. The formed precipitate was filtered off to give 3-amino-6-chloro-pyridine-2-carboxamide (8.1 g). The final filtrate was evaporated to dryness and the residue purified by column chromatography on silica gel (30 g). The compound was eluted with the following solvent systems: CH2Cl2 (200 ml), CH2Cl2/MeOH 100:1 (200 ml). The appropriate fractions were evaporated in vacuo yielding an additional 1.15 g of 3-amino-6-chloro-pyridine-2-carboxamide (total yield 9.25 g, i.e. 90%) which was characterised as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[I-].[K+].[CH2:29]([NH2:32])[CH:30]=[CH2:31]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:32][CH2:29][CH:30]=[CH2:31])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: C=CCN
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 31, 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran is reacted to give 8-nitro-1-[(allylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[OH2:14]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]2[C:4](=[O:13])[O:12][C:5](=[O:14])[NH:6][C:7]=2[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: O
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2c(=O)o1

Procedure:
To a suspension of 4,6-dichloroindolin-2,3-dione (5.95 g) in acetic acid (95 ml) was added chromium trioxide (16 g) over a period of 15 minutes at 60° C. with stirring and the mixture was stirred at 70°-75° C. for 1 hour. After cooling, the reaction mixture was poured into water (360 ml) and the resulting precipitates were collected by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with water and dried. Removal of the solvent gave a residue, which was combined with the precipitates. Recrystallization from isopropyl ether gave 5,7-dichloro-2H-3,1-benzoxazine-2,4(1H)-dione (2.85 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:4][C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+]>CO.CCOC(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2cccc(F)c2)c(Cl)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: OCc1cc(-c2cccc(F)c2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 5-chloro-4-(3-fluorophenyl)picolinate (0.196 g, 0.738 mmol) in MeOH (6 mL) was added NaBH4 (0.152 g, 4.02 mmol). The reaction mixture was stirred at rt for 10 min, and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (1×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% to 60% EtOAc in hexanes) gave (5-chloro-4-(3-fluorophenyl)pyridin-2-yl)methanol.