Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)=[O:27])=[CH:21][CH:20]=1)#[CH:18].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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.[Cu]I>[CH3:35][C:31]1[CH:30]=[C:29]([NH:28][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]#[C:18][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)=[CH:24][CH:23]=2)=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: C#Cc1ccc(NC(=O)Nc2cccc(C)c2)cc1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)Nc2ccc(C#Cc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (50 mg, 0.152 mmol, 1 eq) and 1-(4-ethynylphenyl)-3-(3-methylphenyl)urea (57 mg, 1.5 eq) in anhydrous DMF (1 mL) under nitrogen atmosphere was added triethylamine (0.085 mL, 4 eq), bis(triphenylphosphine)palladium(II) dichloride (10.7 mg, 0.1 eq) and copper(I) iodide (5.8 mg, 0.2 eq). After the reaction mixture was stirred at room temperature for 10 minutes, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (from DCM to MeOH-DCM 1:9). The products' fractions were collected, concentrated, and the solid residue was triturated with EtOAc-Hex (6:1) to give N-(6-{[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]ethynyl}imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide as a brown solid upon filtration in amount of 46 mg.
Reaction SMILES: O.[ClH:2].[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][CH2:20]CC)=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[C:23](OC(NC1CCN(C2C=CC(C(NCCCC)=O)=CC=2)CC1)=O)(C)(C)[CH3:24]>>[ClH:2].[ClH:2].[NH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:18]([CH2:19][CH3:20])[CH2:23][CH3:24])=[O:17])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1
Reactant: CCCCNC(=O)c1ccc(N2CCC(N)CC2)cc1
Reactant: CCCCNC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: O
Product: CCN(CC)C(=O)c1ccc(N2CCC(N)CC2)cc1

Procedure:
By carrying out the operation as described in preparation 11b but using the product from the preceding stage instead of the product from preparation 11a, the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([NH2:15])[C:5](Br)=[C:4]([O:17][CH2:18][CH3:19])[N:3]=1>CO.CN(C=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC(O)=O.CC(O)=O.[Pd]>[NH2:1][C:2]1[C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([NH2:15])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]([O:17][CH2:18][CH3:19])[N:3]=1
Reactant: CCOc1nc(N)c(C(=O)OC(C)(C)C)c(N)c1Br
Agent: [Fe+2]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOc1nc(N)c(C(=O)OC(C)(C)C)c(N)c1C(=O)OC

Procedure:
Prepared analogously to example 377e by carbonylation of the product obtained in (842c) using 1,1′-bis-diphenylphosphino-ferrocene, palladium-II-acetate and TEA in methanol and DMF.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:28]=[CH:27][N:26](COCC[Si](C)(C)C)[N:25]=3)[CH:21]=[C:20]([NH:37][C:38]3[CH:43]=[N:42][CH:41]=[CH:40][N:39]=3)[N:19]=2)[CH3:16])=[CH:11][CH:10]=1>O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)[CH:21]=[C:20]([NH:37][C:38]3[CH:43]=[N:42][CH:41]=[CH:40][N:39]=3)[N:19]=2)[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@H](Nc1cc(-c2ccn(COCC[Si](C)(C)C)n2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1cc(-c2cc[nH]n2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
A mixed solvent of 3 ml of trifluoroacetic acid and 0.3 ml of water was added to 95 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine-2,6-diamine obtained by Step 6, and the mixture was stirred at 60° C. for 1 hour. The solvent was distilled off under reduced pressure, and then the obtained residue was diluted with water and alkalified with a saturated aqueous solution of sodium bicarbonate. The reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 20 mg of the objective compound as pale yellow powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:20]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:19]=[CH:18][CH:17]=2)[N:12]=[C:11]([CH2:25][C:26]2([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:10]=1)C1C=CC=CC=1>O1CCCC1.CO.[OH-].[OH-].[Pd+2]>[C:21]([N:20]1[C:16]([NH:15][C:13]2[N:12]=[C:11]([CH2:25][C:26]3([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]3)[CH:10]=[C:9]([OH:8])[CH:14]=2)=[CH:17][CH:18]=[N:19]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CCOC(=O)C1(Cc2cc(OCc3ccccc3)cc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cc(O)cc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1 g of 1-tert-butyl 4-ethyl 4-((4-(benzyloxy)-6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)piperidine-1,4-dicarboxylate in 10 ml of tetrahydrofuran and 10 ml of methanol was added 300 mg of 20% palladium hydroxide on carbon, followed by stirring the reaction mixture at room temperature for 2 hours under hydrogen atmosphere. Palladium catalyst was filtered off using Celite, washed with methanol, and the filtrate was concentrated in vacuo to give the title compound as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:27]3[C:22]([O:21][CH3:20])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ncccc1B(O)O
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Product: COc1ncccc1-c1c(F)ccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 62.3 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (188 mg, 0.50 mmol) and 2-methoxypyridine-3-boronic acid (155 mg, 1.01 mmol) were reacted. After purification the title compound (110 mg, 62% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (bm, 1H), 8.29 (ad, J=5.0 Hz, 1H), 7.91 (a dd, J=5.2, 9.2 Hz, 1H), 7.67 (a d, J=7.3 Hz, 1H), 7.56 (a t, J=8.9 Hz, 1H), 7.05 (a dd, J=5.0, 7.3 Hz, 1H), 3.88 (s, 3H), 2.96 (m, 1H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=354, HPLC 2.23 min.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:32][C:2]([F:33])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1CNCCNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and [1,4]diazepane following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)([CH2:13][CH:14]=O)[CH2:9]1)=[O:7].[CH2:29]([O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[N:43]1[CH2:49][CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH3:30].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.CO.C(OCC)(=O)C.ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:46]2[CH2:47][CH2:48][CH2:49][N:43]([C:35]3[N:34]([CH2:33][CH2:32][O:31][CH2:29][CH3:30])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:44][CH2:45]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CC=O)(c3ccccn3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccn4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-2-yl)-3-(2-oxoethyl)pyrrolidine (0.29 g, 0.75 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.26 g, 0.91 mmol) silica gel (about 2 g) and 3 Å molecular sieves (about 2 g) in methanol (16 mL). After 18 hours, add sodium cyanoborohydride (0.47 g, 7.5 mmol) and stir. After 7 days, add a solution of 2 M sodium hydroxide and dichloromethane. After 1 hour, filter, separate the layers in the filtrate, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 methanol/ethyl acetate to give the title compound: mp; 40-42° C. Elemental Analysis calculated for C37H48N6O5•0.75 H2O: C, 66.30; H 7.44; N, 12.54; Found: C, 66.33; H, 7.50; N, 12.49.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1.CO>[C:26]([O:20][C:16]1[C:14]2[N:15]=[C:11]([CH2:10][C:9]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[O:12][C:13]=2[CH:19]=[CH:18][CH:17]=1)(=[O:28])[CH3:27]
Reactant: COc1ccc(Cc2nc3c(O)cccc3o2)cc1OC1CCCC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(Cc2nc3c(OC(C)=O)cccc3o2)cc1OC1CCCC1
Yield: 53 %

Procedure:
A solution of 2-(3-cyclopentyloxy-4-methoxybenzyl)-4-hydroxybenzoxazole (200 mg) and acetyl chloride (84 μl) in pyridine (6 ml) was stirred at room temperature, under nitrogen, for 3 hours. The reaction mixture was diluted with methanol (20 ml) and evaporated in-vacuo to yield a yellow solid. The solid was purified by flash chromatography (SiO2; dichloromethane; methanol (50:1)) and crystallized from ether/petroleum ether to yield the title compound (119 mg, 53%) as a white crystalline solid (mp 65-67° C.).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C1(=O)O[CH2:14][CH2:13][O:12]1>>[O:2]1[C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:13][OH:12])=[CH:6][C:4]=2[O:5][CH2:1]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C1OCCO1
Product: OCCOc1ccc2c(c1)OCO2
Yield: 99 %

Procedure:
The title compound was prepared according to the procedure of Example 114, Step 1 starting from sesamol (2.0 g, 14.5 mmol ) and ethylene carbonate (1.0 g, 11.4 mmol): solid; yield 99%. MS m/z 182 (M)+.
Reaction SMILES: [CH:1]([O:4][P:5]([O-:10])[O:6]C(C)C)([CH3:3])[CH3:2].[CH2:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].C(O)(C)C>O>[CH2:11]([NH+:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].[CH:1]([O:4][P:5]([O-:10])[O-:6])([CH3:3])[CH3:2].[CH2:11]([NH+:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]
Reactant: CC(C)OP([O-])OC(C)C
Reactant: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: CC(C)OP([O-])[O-]
Product: CC[NH+](CC)CC
Temperature: 60 °C
Yield: 95 %

Procedure:
Diisopropylphosphite (10.0 g, 0.06 moles), triethylamine (14.6 g, 0.14 moles), isopropanol (20 ml), and water (10 ml) were mixed in a flask under an argon atmosphere and heated at 60° C. for 48 hours. The volatile components were removed under vacuum, leaving a viscous, clear oil. The resulting product was produced in 95% yield (12.8 g) and had the following spectral data:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][C:25]3[NH:26][CH:27]=[CH:28][C:29](=[O:31])[N:30]=3)[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:32].ClC1N=C(O)[C:41]2[C:36](=[CH:37][CH:38]=CC=2)N=1.[O-2].[Ca+2]>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][C:25]3[NH:26][C:27]4[C:28]([C:29](=[O:31])[N:30]=3)=[CH:38][CH:37]=[CH:36][CH:41]=4)[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:32]
Reactant: Oc1nc(Cl)nc2ccccc12
Reactant: Nc1c(Cl)cc(C(=O)OCC2CCN(CCNc3nc(=O)cc[nH]3)CC2)c2c1OCCO2
Agent: [Ca+2]
Agent: [O-2]
Solvent: CC(=O)N(C)C
Product: Nc1c(Cl)cc(C(=O)OCC2CCN(CCNc3nc(=O)c4ccccc4[nH]3)CC2)c2c1OCCO2
Temperature: 140 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of intermediate 15 (2 g), 2-chloro-4-hydroxyquinazoline (1.9 g), N,N-dimethylacetamide (0.3 ml) and calciumoxide (0.4 g) was stirred for 1 hour at 140° C., then cooled and partitioned between water and DCM (+methanol). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The desired fractions were collected and the solvent was evaporated. The residue was suspended in DIPE, filtered off, then dried (vacuum, 60° C.), yielding 1.4 g (50%) [1-[2-[(1,4-dihydro-4-oxo-2-quinazolinyl)amino]ethyl]-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (compound 19).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42]>>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure F, 1-{6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}ethanone (30 mg, 0.0.77 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (44 mg, 0.154 mmol) to afford the desired product (29 mg, 80%) as a yellow solid: 1H NMR (500 MHz, CD3OD TFA-d) δ 9.13 (s, 1H), 8.48 (s, 1H), 8.30 (dd, J=8.7, 1.8 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.77 (s, 2H), 4.66-4.62 (m, 1H), 3.50-3.46 (m, 1H), 2.91 (s, 6H), 2.75 (s, 3H), 2.59-2.55 (m, 2H), 2.34-2.30 (m, 2H), 1.92-1.84 (m, 4H); ESI MS m/z 472 [C25H27Cl2N3O2+H]+; HPLC 98.0% (AUC), tR=9.78 min.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:27]2[C:26]([CH3:28])=[C:25]([CH3:29])[N:24]=[C:23]([NH2:30])[C:22]=2[N:21]=[C:20]1[CH3:31]>>[NH2:30][C:23]1[C:22]2[N:21]=[C:20]([CH3:31])[N:19]([CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:27]=2[C:26]([CH3:28])=[C:25]([CH3:29])[N:24]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 54–68, trans-2-phenylcyclopropyl isocyanate was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 423.2508.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S-:28].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([S:28][CH3:27])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 25 °C
Yield: 65 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (56 mg, 0.13 mmol) in dry DMF (1 mL) at 60° C. was added sodium methanethiolate (9.9 mg, 0.14 mmol). The reaction was heated to reflux for 30 min and then cooled to room temperature. The reaction was quenched with 1M aq. NaOH and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a yellow oil. The oil was purified by flash chromatography (silica gel, 0-33% EtOAc in hexanes) to give 34 mg of the desired product as a colorless oil. MS (ESI) 403 (M+H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16])=[O:8])=[CH:5][CH:4]=1.[NH2:22][OH:23].Cl>C(N(CC)CC)C>[OH:23][NH:22][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=1
Reactant: NO
Reactant: O=C(O)CCCCCCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)c1ccc(C(F)(F)F)cc1)NO
Yield: 35 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 50c for 37 and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound was obtained as light yellow solid in 35% yield: 1H NMR (300 MHz, CD3OD/CDCl3=5/1) δ 8.07 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 3.02 (t, J=7.5 Hz, 2H), 2.12 (t, J=7.5 Hz, 2H), 1.75 (m, 2H) 1.65 (m, 2H), 1.40 (m, 4H); 13C NMR (75.4 MHz, CD3OD/CDCl3=5/1) δ 23.57, 25.03, 28.51, 28.59, 32.50, 38.50, 123.37(q, JCF=273 Hz),125.43 (q, JCF=3.7 Hz), 128.18, 134.09 (q, JCF=32.6 Hz), 139.32, 171.15, 199.93.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C@@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)[CH3:21])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[C@@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)[CH3:21])=[CH:14][CH:15]=1
Reactant: C[C@H](Oc1ccc(F)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(F)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 95.6 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-fluoro-pyridine 310 mg (0.75 mmol) dissolved in toluene (5 mL) were added 0.10 mL (0.98 mmol) of 1-chloroethyl chloroformate and 0.17 mL (0.98 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 230 mg (85%) of the title compound as a light yellow oil. ES-MS m/e: 321.3 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([C:17]2[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:20]1[CH:19]=[CH:18][C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:22][CH:21]=1)([O-:10])=[O:9]
Reactant: OB(O)c1ccc(-c2ccccc2)nc1
Reactant: O=[N+]([O-])c1ccccc1I
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
2-Iodo-1-nitrobenzene (6.88 g, 27.64 mmol), 6-phenyl-3-pyridinylboronic acid (5.5 g, 27.64 mmol), potassium phosphate (17.6 g, 82.91 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.451 g, 0.522 mmol) and Pd2(bda)3 (0.119 g, 0.55 mmol) were to toluene (150 mL) and water (12 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was extracted with ethylacetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethylacetate and hexanes as the eluent. The solvent was removed to give 5.02 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]=O.Cl.[C:16]([O:20][C:21](=[O:28])[C@H:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:23])([CH3:19])([CH3:18])[CH3:17].[Na]>O1CCCC1.C(OCC)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][NH:23][C@H:22]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](NCCN1C(=O)c2ccccc2C1=O)C(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A solution of the product of Example 111-1 (46.5 g, 246.0 mmol) in tetrahydrofuran (900 mL) was treated with L-tert-leucine-t-butyl ester hydrochloride salt (66.1 g, 295.2 mmol, 1.2 equivalents) stirred at 20° C. for 2 hours, treated with sodium triacetoxyborohydrodride (78.2 g, 369.0 mmol, 1.5 equivalents) portionwise over 5 minutes (slightly exothermic), stirred at 20° C. for 2 hours, diluted with ethyl acetate (1 L) and washed with water (1 L). The organic layer was washed with water (1 L), 10% NaHCO3 (2×1 L) and brine (1 L). The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (87 g, 98.2% yield). 1H NMR (CDCl3): δ 7.82 (m, 2 H), 7.70 (m, 2 H), 3.77 (t, 2 H), 2.92 (m, 1 H), 2.73(s, 1H), 2.68(m, 1H), 1.44(s, 9H), 0.86(s, 9H).