Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=O.[CH3:13][C:14]([S:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].CCCCCCC>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[N:19][S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18]
Reactant: O=C1CCOc2ccc(Br)cc21
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CCOc2ccc(Br)cc21
Temperature: 60 °C
Yield: 82.6 %

Procedure:
6-Bromochroman-4-one (5.0 g, 22 mmol) and 2-methylpropane-2-sulfinamide (2.6 g, 22 mmol) were dissolved in dry THF (80 mL). Titanium ethoxide (10 g, 44 mmol) was added. The resulting mixture was heated at 60° C. for 2 days. An additional portion of titanium ethoxide (1.0 g, 8.4 mmol) was added after 12 h. The mixture was mixed with heptane and evaporated onto silica gel. Flash chromatography on silica (0-50% EtOAc in heptane) gave the title compound (6.0 g, 83% yield). 1H NMR (500 MHz, CDCl3) δ ppm 1.34 (s, 9 H) 3.26-3.32 (m, 1 H) 3.47-3.54 (m, 1 H) 4.28-4.40 (m, 2 H) 6.83 (d, 1 H) 7.46 (dd, 1 H) 8.06 (d, 1 H); MS (ES+) m/z 330 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O>[N+:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([NH:1][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:6][C:5]=2[CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2s1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc2cc([N+](=O)[O-])ccc2s1)c1ccccc1
Temperature: 60 °C
Yield: 78.5 %

Procedure:
A mixture of 2-amino-5-nitrobenzothiazole (1.52 g, 7.8 mmol), benzoyl chloride (1.36 mL, 11.7 mmol) and pyridine (15 mL) was heated to 60° C. for 24 h. The mixture was poured into water (250 mL), and the resulting precipitate was separated by filtration to yield N-(5-nitrobenzothiazol-2-yl)benzamide (1:83 g, 6.12 mmol, 78%) as a yellow solid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:11])/[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[O:12]=[C:13]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH2:15][N:14]1[CH2:31][C:32](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[N:11]=[C:32]([CH2:31][N:14]3[CH2:15][CH2:16][CH2:17][C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]3=[O:12])[O:1][N:2]=2)=[CH:5][CH:6]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: N/C(=N\O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(O)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
(Z)—N′,4-Dihydroxybenzimidamide (0.251 g, 1.649 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.510 g, 1.649 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.474 g, 2.473 mmol) were stirred together in dichloroethane at room temperature for 2 hours, then heated to 85° C. for 16 hours. The reaction was cooled and concentrated. The residue was dissolved in dichloromethane (5 mL) and washed with water (3 mL). The organic layer was concentrated and the residue was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow=35 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.95-7.78 (m, 2H), 7.40-7.16 (m, 10H), 6.85-6.71 (m, 2H), 5.93 (s, 1H), 4.88 (s, 2H), 3.64 (t, J=6.5, 2H), 2.78-2.66 (m, 2H), 1.99-1.80 (m, 2H); MS (ESI+) m/z 426.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]([CH3:33])[CH3:32])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.C1C=CC2N(O)N=NC=2C=1.[S:49]1[CH:53]=[CH:52][C:51]([CH2:54][C:55](O)=[O:56])=[CH:50]1>CC(N(C)C)=O>[CH3:32][N:31]([CH2:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:55](=[O:56])[CH2:54][C:51]5[CH:52]=[CH:53][S:49][CH:50]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:33]
Reactant: O=C(O)Cc1ccsc1
Reactant: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5ccsc5)c4)nn4ccccc34)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.7 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine (50 mg, 0.115 mmol) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and 3-thienylacetic acid (48 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (0-100% 9:1:0.1 DCM:MeOH:NH4OH) to afford the title compound (32 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 6H), 3.46 (s, 2H), 3.78 (s, 2H), 6.54 (d, 1H, J=5.31 Hz), 6.90 (dd, 1H, J=1.47, 6.96 Hz), 6.99-7.00 (m, 1H), 7.06 (dd, 1H, J=1.28, 4.94 Hz), 7.22-7.38 (m, 8H), 7.53-7.56 (m, 2H), 7.61-7.63 (m, 1H), 7.77-7.80 (m, 1H), 8.16 (d, 1H, J=5.31 Hz), 8.32-8.35 (m, 1H), 8.46-8.48 (m, 1H). ES-LC/MS m/z=560 [M+H]+.
Reaction SMILES: Cl.Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][C@H:59]([OH:62])[C@@H:58]([CH3:63])[CH2:57]2)CC1>>[OH:62][C@H:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][C@@H:58]1[CH3:63]
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5coc6ccc(Cl)cc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, see example 42) and amine 14 analogously to the method described in example 1.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:10]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1)#[N:11]
Reactant: N#Cc1cccc(O)c1
Reactant: COc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccnc1Oc1cccc(C#N)c1
Temperature: 140 °C
Yield: 72.2 %

Procedure:
2-Bromo-3-methoxypyridine (15 g, 68 mmol) and 3-cyanophenol (8.9 g, 75 mmol) are dissolved in DMF (150 ml), and thereto are added potassium carbonate (28 g, 0.2 mol) and cuprous bromide (10.7 g, 75 mmol), and the mixture is heated under reflux at 140° C. for 1.5 hours. After being allowed to cool, to the reaction solution is added ethyl acetate (1000 ml), and the mixture is washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from isopropyl ether/hexane to give the title compound (11.1 g) as pale brown crystals, m.p. 88-89° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH:3]=1.[F:19][C:20]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:6]1[N:7]=[C:2]([C:26]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([F:19])[CH:27]=2)[CH:3]=[C:4]([NH:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(NC2CCc3ccccc32)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(NC3CCc4ccccc43)nc(N)n2)cc1F
Temperature: 120 °C
Yield: 53.8 %

Procedure:
A mixture of 6-chloro-N4-(2,3-dihydro-1H-inden-1-yl)-2,4-pyrimidinediamine (700 mg, 2.69 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (797 mg, 3.23 mmol) in 1,4-dioxane (150 mL) and a solution of NaHCO3 (903 mg, 10.76 mmol) in water (50 mL) was protected with nitrogen. Pd(Ph3P)4 (31 mg, 0.0269 mmol) was added, and the reaction mixture was heated at 120° C. for 16 hours. The mixture was decanted to remove the solids, and the solution was concentrated to dryness. The crude material was purified by SiO2 chromatography eluting with 1:1 THF:petroleum ether to afford the title compound (500 mg) as a yellow solid. LC-MS (ES) m/z=246 [M+H]+.
Reaction SMILES: N[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[BrH:13].N([O-])=O.[Na+]>O>[Br:13][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cc2nc(Br)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (3 g, 16 mmole) was suspended in 150 ml of water and brought into solution with 2 ml of HBr. Sodium nitrite (3.3 g, 55 mmole) was then added and the mixture was stirred at room temperature for 1 hr. Excess CuBr2 was then added and the mixture was heated on a steam bath for 1 hr. The aqueous solution was extracted with ethyl acetate (3×100 ml), dried with MgSO4, concentrated, and crystallized from ethyl ether to give 1.13 g (26%) of 2-bromo-5,6-dichlorobenzimidazole (7). 1H NMR (DMSO-d6) δ7.81 ppm (s, 2H), 13.62 (s, 1H). GC/MS: m/e 266, 185, 158, 150, 133, 124, 107, 97, 88, 73, 62, 52, 37.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]2.[C:20](=N)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.CCOC(C)=O>[C:20](=[N:1][CH2:2][C:3]1[C:4]([Cl:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH:7]=[CH:6]2)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN)ccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN=C(c3ccccc3)c3ccccc3)ccc21
Temperature: 40 °C
Reaction time: 96 h
Yield: 67.1 %

Procedure:
A mixture of tert-butyl 5-(aminomethyl)-4-chloro-1H-indole-1-carboxylate (1.147 g, 4.087 mmol) and benzophenone imine (0.75 mL, 4.496 mmol) in anhydrous DCM (39.3 mL) was stirred at 40° C. under N2 for 4 d. The reaction mixture was diluted with EtOAc, and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with and EtOAc/heptane gradient (0 to 70% EtOAc) to afford 1.22 g (67%) of tert-butyl 5-[(benzhydrylideneamino)methyl]-4-chloro-1H-indole-1-carboxylate (322) as an oil: 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.5 Hz, 1H), 7.82-7.77 (m, 1H), 7.69 (d, J=7.2 Hz, 2H), 7.60-7.56 (m, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.9 Hz, 2H), 7.37 (d, J=7.0 Hz, 1H), 7.33 (t, J=7.3 Hz, 2H), 7.25-7.20 (m, 2H), 6.66 (d, J=3.7 Hz, 1H), 4.75 (s, 2H), 1.66 (s, 9H); MS (ESI) m/z=445.2 [M+1]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O.[CH:44]([C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1)([CH3:46])[CH3:45]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([NH:51][C:50]4[CH:52]=[CH:53][C:47]([CH:44]([CH3:46])[CH3:45])=[CH:48][CH:49]=4)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)O)c1)C3
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)Nc2ccc(C(C)C)cc2)c1)C3
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 12.6 %

Procedure:
To a mixture of 3-(8,9-dimethoxy-1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid hydrochloride (0.38 mmol, 152 mg), N, N-diisopropylethylamine (1.14 mmol, 0.199 mL), and catalytic DMAP in 2.0 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.494 mmol, 0.293 mL). After 8 min at rt, 4-isopropylaniline (0.57 mmol, 0.081 mL) was added and the reactions continued for 1.8 hours. Then an additional 0.050 mL propylphosphonic anhydride solution and 0.020 mL 4-isopropylaniline was added, the mixture briefly heated to 80° C. 3 times, and then continued at rt for 2 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed eluting with CHCl3/EtOAc/MeOH and then triturated with EtOAc to give the title compound as a light yellow solid (23 mg, 13%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:9][NH2:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CN)c1ccccc1

Procedure:
A solution of the crude phthalimide and hydrazine hydrate (10.0 ml, 177 mmol) in EtOH (200 ml) was stirred at reflux for 1 hour. Once cooled, the mixture was concentrated under reduced pressure. The residue was suspended in 1.5M HCl (200 ml) and washed with CH2Cl2 (50 ml×3). The organic solution was extracted with 4M HCl (50 ml×2). The combined aqueous extracts were made basic with 10M NaOH (100 ml) and extracted with CH2Cl2 (50 ml×4). This organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification gave ((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester as an off-white solid (2.41 g, 51% over 2 steps).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH3:26][NH:27][C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29]>CS(C)=O>[CH3:26][N:27]([C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CN[C@@H](C)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.26 mmol) in DMSO (2 mL) was added DIEA (244 mg, 1.89 mmol), and (S)—N-methyl-1-phenylethanamine (204 mg, 1.51 mmol) with stirring for 3 h at 85° C. in an oil bath. The reaction was then quenched by the addition of water (50 mL). The product was precipitated via the addition of water and collected by filtration to give (S)-methyl 3-(methyl(1-phenylethyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (323 mg, 76%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][CH:9]([C:17]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:10]([O:12]C(C)(C)C)=[O:11]>C(Cl)Cl>[CH3:8][CH:9]([C:17]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])[C:10]([OH:12])=[O:11]
Reactant: CC(C)CC1(C(C)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC1(C(C)C(=O)O)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 11.9 %

Procedure:
TFA (10.0 mL) is added to a solution of tert-butyl α-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (780 mg, 2.09 mmol) and CH2Cl2 (10 mL) at 0° C. The solution is stirred for 2.5 hours at 0° C. and 1.5 hours at room temperature. After concentration, the residue is partitioned between EtOAc and water. The organic layer is extracted several times with 10% NaOH, the combined basic layers acidified (4N HCl), and the acidic layers extracted several times with CH2Cl2. The CH2Cl2 layers are dried (MgSO4), filtered, and concentrated to provide 79 mg (12%) of the title compound as a white solid (mp 94°-95° C.).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH2:13]([C:15]1([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]([CH3:21])[C:16]1=[O:22])[CH3:14]>O1CCCC1.CCCCCC>[CH2:13]([C:15]1([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]([CH3:21])[C:16]1([C:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6])[OH:22])[CH3:14]
Reactant: C#CC(O)CCC
Reactant: CCC1(C)CCCC(C)C1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(O)C#CC1(O)C(C)CCCC1(C)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.2 G (0.41M) of 1-hexyn-3-ol in 200 ml of anhydrous tetrahydrofurane (THF) have been placed in a three-necked reaction vessel and cooled to -70°. At this temperature there were added under stirring 390 ml (0.91M) of a 15% solution of butyl-lithium in hexane and the temperature was then raised to about 20° within one night. A solution of 40 g (0.26M) of 2-ethyl-2,6-dimethylcyclohexanone in 90 ml of THF-75/25 isomeric mixture of the following compounds ##STR15## was added dropwise to the reaction mixture cooled again to -70°. After having been kept under stirring for 3 h at -70° and overnight at room temperature, the mixture was poured onto ice, extracted with ether, washed with brine until neutrality, dried over Na2SO4, filtered and concentrated.
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O[C:16](=[O:33])[CH2:17][CH:18]1[CH2:23][CH2:22][C:21]([N:30]([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)C.[Cl-].[NH4+]>C1COCC1>[CH3:32][N:30]([CH3:31])[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:22][CH2:23][CH:18]([CH2:17][C:16]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:33])[CH2:19][CH2:20]1
Reactant: CCOC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Reactant: Nc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)Nc2ccccc2)CC1
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6 M solution in hexane; 7.1 ml; 11.4 mmol) was added dropwise at 0° C. to a solution of aniline (0.53 g; 5.7 mmol) in 10 ml THF. The mixture was allowed to come to RT and was subsequently stirred for 1 h. A solution of (4-dimethylamino-4-phenyl-cyclohexyl)-acetic acid ethyl ester (1.5 g; 5.2 mmol) in 15 ml THF was added dropwise at −78° C. The mixture was subsequently stirred for 1 h and then allowed to come to RT. It was hydrolysed with ammonium chloride solution and extracted with MC. After concentration, the crude product was chromatographed on silica gel (eluent:ether). 308 mg (18%) of the less polar and 620 mg (36%) of the more polar diastereoisomer were obtained.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=2)[N:5]2[CH:17]=[CH:18][CH:19]=[C:4]12)[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[Cl:32]>>[Cl:32][C:23]1[CH:24]=[C:25]([S:28]([N:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=3)[N:5]3[CH:17]=[CH:18][CH:19]=[C:4]3[CH:3]2[CH2:1][CH3:2])(=[O:30])=[O:29])[CH:26]=[CH:27][C:22]=1[O:21][CH3:20]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: CCC1Nc2cc(C(F)(F)F)ccc2-n2cccc21
Product: CCC1c2cccn2-c2ccc(C(F)(F)F)cc2N1S(=O)(=O)c1ccc(OC)c(Cl)c1

Procedure:
The title compound was prepared from the product of Example 55, step 1 and 4-methoxy-3-chloro benzenesulfonyl chloride according to the procedure of Example 4 to yield light brown crystals, mp 126-129° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[CH:10][N:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]>CO>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[C:6]=1[C:5]([OH:28])=[O:4]
Reactant: COC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
NaOH (3.6 mL, 2M solution in H2O, 7.2 mmol) was added to a solution of 3-(2-chloro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid methyl ester (343 mg, 0.71 mmol) in MeOH (3 mL) and stirred overnight at 60° C. The MeOH was removed and the aqueous solution was acidified with concentrated HCl. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to afford the desired product (253 mg, 76%). LC-MS (M+H=469, obsd.=469).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=12.C(N(C(C)C)CC)(C)C.[O:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1.O>CN1CCCC1>[CH2:18]([N:15]1[C:4]2=[N:5][C:6]([CH2:13][CH3:14])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:35][CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)=[C:3]2[CH:17]=[N:16]1)[CH3:19]
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Yield: 111.3 %

Procedure:
To a solution of ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (380 g) in 1-methylpyrrolidine (3,166 mL) was added diisopropylethylamine (469.8 mL) and tetrahydro-2H-pyran-4-ylamine (163 g) and the mixture was heated at reflux for 16 h. The cooled mixture was treated with water (12 L) and extracted with ethyl acetate (6×1250 mL). The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated to dryness to afford 520 g of a dark brown oil. The product was purified by flash chromatography on silica using ethyl acetate/cyclohexane @ 1:4-1:2 as eluant to afford 336 g of the title compound. LC-MS m/z 347 (M+H)+, 3.02 min (ret time).