Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCC(N[C@H](C([NH:17][C@H:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:19]([CH3:21])[CH3:20])=O)CC(=O)OC(C)(C)C)=O.[NH:29]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:30]([C:39]([OH:41])=O)[CH2:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].N[C@H](C(OC(C)(C)C)=O)C(C)C>>[NH:29]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:30]([C:39]([NH:17][C@H:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:41])[CH2:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)[C@H](N)C(=O)OC(C)(C)C
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A diester such as H-Gly-Asp(OtBu)-Val-OtBu can be prepared by condensing Z-Asp(OtBu)-OH and H-Val-OtBu to give Z-Asp(OtBu)-Val-OtBu, hydrogenolyzing the latter, coupling the resulting H-Asp(OtBu)-Val-OtBu with Z-Gly-OSu to give Z-Gly-Asp(OtBu)-Val-OtBu and hydrogenolyzing the latter.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])(=[O:3])[CH3:2].[K+].[Br-]>>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2Cl)c(NC(C)=O)c2ccc(Cl)cc21
Agent: [Br-]
Agent: [K+]
Product: CC(=O)Nc1c(C(=O)c2ccccc2Cl)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-2-(2-chlorobenzoyl)-1-(ethoxycarbonyl)indole (step 1). 1H-NMR (CDCl3) δ: 9.58 (1H, br s), 8.51 (1H, br s), 8.19 (1H, d, J=8.8 Hz), 7.52-7.03 (6H, m), 2.18 (3H, s) IR (KBr) ν: 3300, 1680, 1620, 1580, 1540, 1340, 1320, 1240, 1060, 1020, 920, 760, 740 cm−1
Reaction SMILES: ClC1C=CC(C(=O)CCC2C=CC3C(=CC=CC=3)C=2)=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]/[C:31](/[C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30]/[C:31](/[C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[CH:32]\[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:28]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)cc1)c1ccc2ccccc2c1
Agent: O=C(CCc1ccc2ccccc2c1)c1ccc(Cl)cc1
Product: CCOC(=O)/C=C(\CCc1ccc(Cl)cc1)c1ccc2ccccc2c1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 1-(4-chlorophenyl)-3-(2-naphthalenyl)propan-1-one, (Z)-ethyl 5-(4-chlorophenyl)-3-(2-naphthalenyl)pent-2-enoate and (E)-ethyl 5-(4-chlorophenyl)-3-(2-naphthalenyl)pent-2-enoate were obtained as colourless oils.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:3]=1.Br[C:16]1[N:40]=[C:19]2[C:20]([C:25]3[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=3)[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][C:22]([CH3:24])=[CH:23][N:18]2[N:17]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[O-]C1C=CC=CC=1.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C(Cl)Cl>[CH3:24][C:22]1[CH:21]=[C:20]([C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])[C:19]2[N:18]([N:17]=[C:16]([NH:14][CH:11]3[CH2:12][CH2:13][N:8]([C:4]4[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=4)[CH2:9][CH2:10]3)[N:40]=2)[CH:23]=1
Reactant: Cc1cc(N2CCC(N)CC2)ncn1
Reactant: Cc1cc(-c2cccc(CNC(=O)OC(C)(C)C)c2)c2nc(Br)nn2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(-c2cccc(CNC(=O)OC(C)(C)C)c2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1

Procedure:
A solution of 1-(6-methylpyrimidin-4-yl)piperidin-4-amine (52.5 mg, 273 μmol), tert-butyl 3-(2-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzylcarbamate (114 mg, 273 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.6 mg, 21.9 μmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (11.3 mg, 10.9 μmol) and sodium phenoxide (50.1 mg, 410 μmol) in dioxane (3 mL) was degassed three times and reacted at 140° C. under an atmosphere of nitrogen in a microwave oven for 1 hour. The title compound was obtained a light yellow solid (46 mg, 32%) after column chromatography on silica gel using a gradient from methylenechloride to a mixture of methylenechlorid/methanol 19:1 (v/v) as eluent.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][C@@H:5]([C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=3)[N:15]=[CH:14][CH:13]=2)=[O:10])[CH2:4]1.[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[OH:8][C@H:7]1[C@@H:3]([CH2:2][NH:1][CH2:35][C:32]2[CH:33]=[CH:34][C:28]3[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=3[N:31]=2)[CH2:4][C@H:5]([C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=3)[N:15]=[CH:14][CH:13]=2)=[O:10])[CH2:6]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc(NC(=O)[C@H]3C[C@H](CN)[C@H](O)C3)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(NC(=O)[C@H]3C[C@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@H](O)C3)c2n1
Reaction time: 24 h
Yield: 17.4 %

Procedure:
To a stirred solution of (±)-(1S,3R,4R)-3-(aminomethyl)-4-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]cyclopentanecarboxamide (0.48 g, 1.51 mmole) in dry CH2Cl2 (50 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.29 g, 1.51 mmole). After 24 h, at RT was added NaBH4 (0.063 g, 1.66 mmole). After 4 h, the reaction solution was concentrated under vacuum to a solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.13 g, 17%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.68 (d, J=5.1 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 4.12 (s, 3H), 3.92 (m, 3H), 3.49 (s, 2H), 3.38 (m, 1H), 2.95 (m, 2H), 2.39 (m, 1H), 2.50 (m, 4H), 1.91 (m, 1H). LC-MS (ES) m/e 495 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:8]([NH:17][C:18]2[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1NC(=O)C1(C)CCCCC1

Procedure:
A mixture of 32.7 grams (0.203 moles) of 1-methyl-1-cyclohexanecarboxylic acid chloride, 15.2 grams (0.11 mole) of anhydrous potassium carbonate and 21.8 grams (0.203 mole) of o-toluidine in 260 ml. of dry toluene is stirred and refluxed for 2.5 hours. The inorganic salts are removed by filtration and the filtrate is concentrated in vacuuo. The residue yields from diethyl ether-pentane 40.5 grams (87%) of N-(1-methylcyclohexyl carbonyl)-o-toluidine; m.p. 138° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=4)(=[O:28])=[O:27])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtained in Example 214) and 4-methoxybenzenesulfonyl chloride according to the procedure of Example 215 as a crystalline solid; 1H NMR (300 MHz, DMSO-d6) δ 1.65 (t, J=5.6 Hz, 4 H), 3.15 (t, J=5.6 Hz, 4 H), 3.79 (s, 3 H), 3.88 (s, 4 H), 6.69 (d, J=9.0 Hz, 2 H), 9.63 (s, 1 H); MS (ES) m/z: 405.3 (MH+); HRMS Calcd. for C20H24N2O5S (M+): 404.1406. Found: 404.1402. Anal. Calcd. for C20H24N2O5S: C, 59.39; H, 5.98; N, 6.93. Found: C, 59.48; H, 6.03; N, 6.85.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Li+]>O1CCOCC1>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CCOCC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(morpholin-4-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (Step A, 200 mg, 0.268 mmol) was dissolved in 1,4-dioxane (5.0 mL). Lithium hydroxide (0.5M, 2.4 mL, 1.20 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by adding 1.20 mL of 1N HCl, followed by water. The aqueous reaction mixture was extracted with ethyl acetate, then dried over sodium sulfate, filtered and evaporated. Purified on BIOTAGE SNAP C18 column, eluting with 40-100% CH3CN/water (0.05% TFA) and recovering purified fractions by partitioning them between pH 7 phosphate buffer and ethyl acetate. Extracted the aqueous a second time with ethyl acetate, then washed the combined organics with pH 7.0 buffer and brine. The organic was dried over sodium sulfate, filtered and evaporated to give the titled compound. LCMS (M+H)+: 732.5. 1H NMR (CDCl3, 500 MHz): δ 8.22 (d, 1H), 8.20 (s, 1H), 8.03 (s, 1H), 7.99 (d, 1H), 7.88 (s, 1H), 7.72 (s, 2H), 7.48 (d, 1H), 7.35 (d, 1H), 5.64 (d, 1H), 4.76 (d, 1H), 4.32 (m, 1H), 4.00 (m, s, 4H), 3.86 (m, 4H), 3.81 (m, 4H), 2.39 (s, 3H), 0.72 (d, 3H). RTA IC50: 13 nM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][CH2:31][CH2:32][OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:30][CH2:31][CH2:32][OH:33])[N:13]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reactant: NCCO
Product: O=c1ccc2c(-c3ccccc3Cl)nc(NCCO)nc2n1-c1ccccc1Cl

Procedure:
The product of Example 47, and 2-aminoethanol were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.17 (m, 2H), 3.48 (m, 2H), 6.08 (br s, 1H), 6.45 (d, 1H, J=9.6 Hz), 7.26-7.67 (m, 9H). LC MS (m/e)=427 (MH+).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:2]([O:1][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1)[CH3:3]
Reactant: Nc1cccc(Cl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
In a vial in a water bath, a 21% wt solution of sodium ethoxide in ethanol (1.08 g, 1.25 mL, 15.9 mmol) was diluted in ethanol (4 mL) and stirred at 25° C. for 10 min then 6-chloropyridin-2-amine (2.0 g, 15.6 mmol) was added in a single portion. After 3 h the reaction mixture was transferred to a sealed flask and was stirred at 130° C. for 18 h. A second portion of 21% wt solution of sodium ethoxide in ethanol (1.08 g, 1.25 mL, 15.9 mmol) was added and the reaction was stirred at 130° C. for another 36 h. Finally, a third portion of a 21% wt solution of sodium ethoxide in ethanol (3.18 g, 3.66 mL, 46.7 mmol) was added and the mixture stirred at 140° C. for 6 h then at 130° C. for 18 h. The mixture was cooled, concentrated onto silica gel, and purified by chromatography (silica, Analogix 120 g, 0 to 100% ethyl acetate in hexanes, 60 min) to give 6-ethoxypyridin-2-amine (819 mg, 36%) that was used directly without further purification. MS (EI/CI) m/z: 139 [M+H].
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(O)c1C#N
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccnc(Cl)c1C#N
Yield: 89.2 %

Procedure:
To a 250 mL flask equipped with a magnetic stirrer was added 10 g of 2-hydroxy-4-methyl-3-pyridinylcarbonitrile (8) and 60 mL of phosphorous oxychloride. The mixture was refluxed for one hour. The excess POCl3 was distilled under reduced pressure. The residue was poured into water. The crystalline material was filtered and dried at to give 10.2 g (89.2%) of (9). m.p.: 109-110° C., NMR (DMSO); ppm: 2.56 (s,3H); 7.6 (bs,1H); 8.56 (m,1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][O:10][CH2:9][CH2:8][NH:7]1)[CH3:2].C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](Cl)=[O:34])=[CH:23][CH:22]=1>ClCCl.O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:33]([C:28]1[N:29]=[C:30]([CH3:32])[S:31][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=1)=[O:34])[CH3:2]
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: CCOC(=O)CC1COCCN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC1COCCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1
Reaction time: 16 h

Procedure:
Morpholin-3-ylacetic acid ethyl ester Chem Pharm Bull 94, 31(1), 1983 (2.10 g) was dissolved in dichloromethane (50 ml) and treated with triethylamine (1.33 g). The mixture was cooled (ice bath) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (1.53 g) in dichloromethane (10 ml) added. The mixture was stirred for 16 h, diluted with water and the organic phase separated. The aqueous phase was extracted with dichloromethane (2×100 ml), the organic phases combined, dried (Na2SO4) and solvent removed at reduced pressure. the residue was column chromatographed (silica gel, 40% ethyl acetate:pentane ˜60% ethyl acetate pentane eluant) to give the title compound (1.46 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[CH3:22][C:20]1[NH:19][N:18]=[C:17]([NH:16][C:4]2[N:3]=[C:2]([NH:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:21]=1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: N#Cc1ccc(N)cc1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Nc3ccc(C#N)cc3)c2cc1OC

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-amino-benzonitrile to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-6,7-dimethoxy-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 401(MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1C[C@H](O)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 65.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (65.3 mg, 0.103 mmol) prepared in Example 161c, triethylsilane (0.050 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (1.0 mL), to yield the title compound (32.6 mg, 71%) as a colorless solid.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][CH:3]=1.Br[C:8]1[C:24]([O:25][CH2:26][C@@H:27]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:23][C:11]2[N:12]([CH3:22])[C:13](=[O:21])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][C:15]=3[CH3:20].[Cl-].[Li+]>O1CCOCC1>[CH3:20][C:15]1[N:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[C:13](=[O:21])[N:12]([CH3:22])[C:11]1[CH:23]=[C:24]([O:25][CH2:26][C@@H:27]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:28][CH:29]([CH3:31])[CH3:30])[C:8]([C:2]3[S:6][CH:5]=[N:4][CH:3]=3)=[CH:9][C:10]2=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Reactant: Brc1cncs1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(-c3cncs3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
5-Bromothiazole (0.050 g, 0.305 mmol) and hexamethyltin (0.158 mL, 0.762 mmol) were taken up in 1,4-dioxane (1 mL) and purged with nitrogen for 10 min. Tetrakis (triphenylphosphine)palladium (0.035 g, 0.030 mmol) was added and the reaction mixture was stirred for 2 h at rt. (S)-tert-butyl (1-((9-bromo-4,6-dimethyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.158 g, 0.305 mmol) and lithium chloride (0.013 g, 0.305 mmol) were added and the mixture was purged with N2 for 10 min. The reaction mixture was then heated for 16 h at 90° C. After cooling, the reaction mixture was filtered through diatomaceous earth (Celite®) and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford (S)-tert-butyl 1-(4,6-dimethyl-5-oxo-9-(thiazol-5-yl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yloxy)-4-methylpentan-2-ylcarbamate (40 mg, 0.053 mmol, 18% yield) as a yellow solid. LC/MS (ESI) m/e 23.6 [(M+H)+, calcd for C28H35N4O4S 523.2]; LC/MS retention time (method E): tR=1.09 min.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33]1[C:42]([OH:43])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH:35]=[CH:36][N:37]=[CH:38]2.[C:44]([N:51]1[CH2:56][CH2:55][CH:54](O)[CH2:53][CH2:52]1)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].C(N(CC)CC)C>ClCCl>[C:47]([O:46][C:44]([N:51]1[CH2:56][CH2:55][CH:54]([O:43][C:42]2[C:33]([Br:32])=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH:38]=[N:37][CH:36]=[CH:35]3)[CH2:53][CH2:52]1)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc2cnccc2c1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2Br)CC1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
3.75 mL (4.15 g, 23.8 mmol) of diethyl azo dicarboxylate were added to 12.7 g (19.9 mmol) of polymer-bound triphenylphosphine (PS—PPh3, approx. 1.6 mmol/g, Argonaut) in 250 mL of dichloromethane at 0° C. and stirred for 15 min. 4.45 g (19.9 mmol) 5-bromo isoquinoline-6-ol (9), 4.0 g (19.9 mmol) Boc-(4-hydroxy)piperidine and 4.1 mL (3.0 g, 29.8 mmol) triethyl amine were added. The mixture was shaken for 16 h. The polymer was removed by filtration through Celite and the solvents were distilled off. 20 mL dichloromethane were added and the precipitate was isolated by filtration. The crude product (8 g) was purified by flash chromatography using ethyl acetate/n-heptane as eluent to give 4.78 g (60%) of compound 11.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:26][CH:27]=1.O>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1)[O:19][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=2)=[N:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cn2)cc1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
15 mg (0.60 mmol) of 95% sodium hydride were added at 0° C. to a solution of 116 mg (0.50 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 136 mg (0.50 mmol) 5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyridine were given to the reaction mixture and stirring continued at r.t overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether to give 165 mg (71%) of the title compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.F[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[I:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)[CH:24]=1
Reactant: Fc1cc(I)ccn1
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cn(-c3cc(I)ccn3)ccc2=O)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one (7.30 g, 31.6 mmol), 2-fluoro-4-iodopyridine (10.56 g, 47.35 mmol), and K2CO3 (10.9 g, 79 mmol) in DMSO (80 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was washed with EtOAc and filtered, and the collected solid dried to give 4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one. 1H-NMR (DMSO, 400 MHz) δ 8.41 (dd, J=8.0, 2.4 Hz, 1H), 8.30 (s, 1H), 8.20 (m, 2H), 7.81 (dd, J=4.0, 0.8 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.28 (d, J=7.6 Hz, 1H), 4.96 (s, 2H), 3.72 (s, 3H). MS (M+H)+ 435.1.