Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2].I[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:16][CH:15]=1>CN(C=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:24]([NH:23][CH:21]([CH3:22])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:15][CH:16]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NC(C)Cc1ccc(I)cc1
Reactant: C#Cc1cccc(C(=O)OC)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)c1
Temperature: 25 °C

Procedure:
To 10.0 g (63.4 mmol) methyl 3-ethynylbenzoate (J. Org. Chem. 1981, 46, 2280-6) and 7.00 g (23.1 mmol) N-(1-(4-iodo-phenyl)propan-2-yl)acetamide (I52.1) in 80 mL DMF are added 100 mL TEA, 250 mg (1.31 mmol) CuI and 1.20 g (1.71 mmol) bis(triphenylphosphine)-palladium (II) chloride. After stirring over night r.t. the solvents are removed under reduced pressure. The residue is partitioned between EtOAc and diluted aq. NH4Cl solution. The organic layer is separated and the aq. layer is extracted with EtOAc (2×). The org. layers are combined, washed with brine, dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, EtOAc 100%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5](O)[CH2:4][C:3]1([CH3:12])[CH3:11].N(OC(C)(C)C)=O.[CH2:20]([O:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1N)[CH:21]=[CH2:22]>ClC1C=CC=CC=1>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH:21]([CH2:22][O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:20]1
Reactant: C=CCOc1ccccc1N
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: CC(C)(C)ON=O
Solvent: Clc1ccccc1
Product: CC1(C)CCCC(C)(C)N1OCC1COc2ccccc21
Yield: 61.4 %

Procedure:
The procedure of Example 1 is repeated using 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 3.10 g (30 mmol) of tert-butyl nitrite, 7.5 mg (0.012 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) mmol) in 100 mL of chlorobenzene and 5.60 g (25 mmol) of 2-allyloxyaniline in 20 mL of chlorobenzene. The crude product obtained is purified by vacuum flash chromatography (25% ethyl acetate/heptane) to give 2.22 g of a viscous liquid in 61.5% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH3:26])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH3:26])=[CH:21][CH:20]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(N)cc1
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Yield: 71.8 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (347 mg, 1.12 mmol) was reacted with tert-butyl 2-(4-aminophenyl)propan-2-ylcarbamate (420 mg, 1.68 mmol) to afford the desired product (422 mg, 63%) as a yellow solid: ESI MS m/z 524 [C27H30BrN3O3+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13].[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1O
Reactant: O=C(O)c1ccncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1Cl
Temperature: 80 °C
Yield: 57.3 %

Procedure:
A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 g of 3-chloroisonicotinic acid, 0.56 g of WSC and 5 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 3-chloro-N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[S:9][CH:10]=1.[CH3:14]O>>[OH:5][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1
Reactant: O=C(O)c1cc(O)cs1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)cs1
Temperature: 25 °C

Procedure:
Thionyl chloride (1.6 ml) was added dropwise to a methanol solution (20 ml) of 4-hydroxythiophene-2-carboxylic acid (1.1 g, 7.6 mmol) under ice cooling. The solution mixture was refluxed with heating for 5 hours. The reaction solution was cooled to room temperature, poured into ice water and extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) and concentrated/dried under reduced pressure to obtain methyl 4-hydroxythiophene-2-carboxylate (0.7 g) as white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C(OCC)(=O)[CH2:24][CH2:25][C:26]([O:28]CC)=[O:27].Cl>O.C(O)(C)(C)C>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc(C(=CCC(=O)O)c2ccc(C)cc2)cc1

Procedure:
To a 500 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 29.7 grams (141 mmol) 4,4'-dimethylbenzophenone and 141 mL t-butanol forming a solution, followed by 17.4 grams (155 mmol) potassium t-butoxide and 29.5 grams (170 mmol) diethyl succinate. The reaction was refluxed for 18 hours, cooled, and acidified with 6N hydrochloric acid, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated, and the residue taken up in 200 mL glacial acetic acid. It was then treated with 70 mL 48% hydrobromic acid and refluxed for 36 hours. The reaction was cooled, partitioned between water and ethyl acetate, and the combined organic layers washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/methanol as eluant to afford the product as low melting solid, 25.0 grams (66%), Rf =0.25 in 5% methanol/methylene chloride on silica gel. This material was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[C:20](=[O:21])[CH2:19][NH:18][C:17]3=[O:22])[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][C@H:26]([CH2:34][OH:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[N+:36]([C:39]1[N:40]=[CH:41][NH:42][CH:43]=1)([O-:38])=[O:37].C1(C(C2C=CC=CC=2)CNC2N=C(N3C=C([N+]([O-])=O)C=N3)N=C3C=2N=CN3[C@@H]2C[C@H](NC(=O)CO)[C@@H](O)[C@H]2O)C=CC=CC=1>>[OH:23][C@H:13]1[C@@H:12]([OH:24])[C@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([N:42]2[CH:43]=[C:39]([N+:36]([O-:38])=[O:37])[N:40]=[CH:41]2)=[N:3][C:4]=3[NH:25][C@H:26]([CH2:34][OH:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][C@@H:14]1[N:16]1[C:20](=[O:21])[CH2:19][NH:18][C:17]1=[O:22]
Reactant: O=C1CNC(=O)N1[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc([N+](=O)[O-])cn4)nc32)[C@H](O)[C@@H]1O
Product: O=C1CNC(=O)N1[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(-n4cnc([N+](=O)[O-])c4)nc32)[C@H](O)[C@@H]1O

Procedure:
3-{(1S,2R,3S,4R)-4-[2-Chloro-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-imidazolidine-2,4-dione (Intermediate VB) and 4-nitro-imidazole, as described for N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate QD).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([OH:35])[CH:34]=1)[C:29](O)=[O:30]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:29](=[O:30])[C:28]2[CH:27]=[C:26]([OH:25])[CH:34]=[C:33]([OH:35])[CH:32]=2)[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Reactant: O=C(O)c1cc(O)cc(O)c1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3cc(O)cc(O)c3)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 3,5-dihydroxybenzoic acid as brown solid (29%). MS 468 (MH+).
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[CH:47]([C:50]1[CH:63]=[CH:62][C:53]([CH2:54][S:55][CH2:56][C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:52][CH:51]=1)([CH3:49])[CH3:48]>C(O)C>[CH3:29][N:30]([CH3:42])[C:31](=[CH:32][CH:33]=[C:56]([S:55][CH2:54][C:53]1[CH:62]=[CH:63][C:50]([CH:47]([CH3:48])[CH3:49])=[CH:51][CH:52]=1)[C:57]([O:59][CH2:60][CH3:61])=[O:58])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)CSCc1ccc(C(C)C)cc1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1ccc(C(C)C)cc1
Yield: 62.2 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (21 cc) and ethyl (4-isopropylbenzylthio)acetate (8.8 g) in ethanol (100 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (80:20 by volume) as eluent, diethyl 2-dimethylamino-5-(4-isopropylbenzylthio)-2,4-hexadienedioate (8.8 g) is obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.CCN(CC)CC.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1.C(Cl)Cl>[N:26]1([C:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:10]3[N:9]=[C:8]([N:4]4[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][S:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)(=[O:47])=[O:46])[CH2:3]4)[CH:16]=[CH:15][C:11]=3[C:12]([NH2:14])=[O:13])=[CH:23][CH:22]=2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCC[C@@H](NS(=O)(=O)c3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (30 mg, 0.071 mmol) and Et3N (0.049 mL, 0.353 mmol) in THF (2 mL) was added benzenesulfonyl chloride (18.72 mg, 0.106 mmol). The solution was stirred at rt for 10 min. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified (ISCO, 5% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to obtain 30 mg of (R)-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(3-(phenylsulfonamido)piperidin-1-yl)nicotinamide as a light yellow solid. LCMS: (M+H)+=465.40. 1H NMR (400 MHz, CDCl3) δ ppm 11.13 (1H, s), 7.84-7.90 (2 H, m), 7.58-7.63 (2H, m), 7.54-7.57 (1H, m), 7.44-7.52 (3H, m), 7.33 (2H, d, J=8.56 Hz), 5.99 (1H, d, J=8.81 Hz), 5.71-5.87 (2H, m), 3.85 (1H, d, J=10.83 Hz), 3.38-3.79 (12H, m), 1.67-1.79 (2H, m), 1.44-1.57 (2H, m).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:35]2[C:36]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:37][CH:38]=[CH:39][C:34]=2[CH3:33]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3I)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3I)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 619.6 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[C:2]#[CH:3].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>CN(C=O)C.CCN(CC)CC.CCOC(C)=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.[Cu]I>[F:9][C:10]1[C:11]([C:3]#[C:2][CH2:1][NH:4][S:5]([CH3:8])(=[O:7])=[O:6])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCNS(C)(=O)=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNS(C)(=O)=O)c21

Procedure:
Using Method C above, N-(Prop-2-ynyl)-methanesulfonamide (80 mg, 0.62 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (Z)-N-[3-[5-Fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-2,3-dihydro-1H-indol-4-yl]-prop-2-ynyl]-methanesulfonamide was obtained after HPLC purification with 40% EtOAc in hexanes and precipitation out of THF with excess of pentane. (Yield 48 mg, 59%).
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.[CH3:23][OH:24]>>[CH3:23][O:24][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
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: CO
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 315(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1
Reactant: Oc1cccc(Br)c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccn2)c1
Yield: 96.6 %

Procedure:
3-Bromophenol (1.00 g, 5.8 mmol), 2-picolyl chloride hydrochloride (950 mg, 5.8 mmol) and potassium carbonate (3.20 g, 23 mmol) were stirred together in DMF (10 mL) at room temperature overnight. The solvent was removed in vacuo, azeotroping with xylene to remove the last traces of DMF. The residual material was partitioned between ethyl acetate (70 mL) and water (70 mL), then the organic phase was washed with saturated sodium chloride solution (1×50 mL), was dried over magnesium sulfate, and was concentrated in vacuo to afford 2-(3-bromophenoxymethyl)pyridine (1.48 g, 97%). m/z (ES+) 265 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][S:11]([O-:13])=[O:12].[Na+]>CN(C)C=O>[CH3:10][S:11]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1)(=[O:13])=[O:12]
Reactant: CS(=O)[O-]
Reactant: BrCc1cccc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 3-bromobenzyl bromide (5.0 g, 20 mmol) in dry dimethylformamide (50 ml) at room temperature under an atmosphere of argon was treated portionwise with sodium methanesulfinate (2.0 g, 20 mmol) with stirring. The mixture was stirred at room temperature for 16 h, and then at 50° C. for 0.5 h. The reaction mix was allowed to cool to room temperature and then partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulfate and the solvent removed under reduced pressure to give an oil which was purified by column chromatography on a 50 g isolute silica sep-pak column eluting from 0-100% ethyl acetate in petroleum ether to give the title compound as an off-white solid (3.34 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH2:18][CH3:19])[N:12]=[C:11]([S:20][CH3:21])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:22]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[C:14]([C:15]([NH:31][CH2:30][CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:17])=[C:13]([CH2:18][CH3:19])[N:12]=[C:11]([S:20][CH3:21])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: NCCCc1ccccc1
Reactant: CCc1nc(SC)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCc1nc(SC)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
183 mg (0.533 mmol) of 4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio)-pyrimidine-5-carboxylic acid and 86.5 mg (0.640 mmol) of phenylpropylamine were dissolved in 10 ml of dichloromethane. 153 mg (0.800 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter referred to as WSC hydrochloride) was added under cooling with ice and stirred at room temperature overnight. After concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate. The reaction mixture was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH2:30])=[CH:24][NH:25]2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([NH:30][CH2:29][CH2:28][C:23]2[C:22]3[C:26](=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[NH:25][CH:24]=2)=[O:13])[CH:7]=1
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(CCNC(=O)c3cc(Cc4cccc(F)c4)on3)c[nH]c2c1
Yield: 34.6 %

Procedure:
A solution of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(6-methoxy-1H-indol-3-yl)ethanamine (0.054 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisopropylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.035 g (38%) of the title compound as a white solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C1COCC1>[CH3:15][C:11]1[C:10]2[N:9]([C:20](=[O:19])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:16]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cccnc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(C)cccn2c1=O
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of LDA (1.8 M in THF/heptane/ethylbenzene, 64.8 mL, 117 mmol) in THF (200 mL) at −78° C. was added 2,3-lutidine (10.6 mL, 93.3 mmol) in THF (62 mL) dropwise over 10 min. After stirring the mixture an additional 40 min at −78° C., diethyl ethoxymethylenemalonate (21.7 mL, 107 mmol) in THF (30 mL) was added slowly over 15 min. The mixture was warmed slowly to rt over 2.5 h. The resulting solution was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2 (3×). The combined extracts were dried (Na2SO4) and concentrated. The intermediate was dissolved in o-xylene (93 mL) and heated to reflux for 16 h. After cooling to rt, the mixture was concentrated. Purification by silica gel chromatography eluting with 0-5% MeOH:CH2Cl2 afforded ethyl 9-methyl-4-oxo-4H-quinolizine-3-carboxylate as a yellow solid.