Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:8])(=O)C>[OH-].[K+]>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]([CH3:8])[CH2:6][CH2:5][NH2:4])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1
Reactant: CC(=O)NCCC(C)c1ccc(-c2ccc(F)cc2)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 28.5 g of 1-acetamido-3-(4'-fluoro-4-biphenylyl)-butane in 800 ml of 10% methanolic KOH solution is boiled for 48 hours. The solution is concentrated and worked up using water and ether to give 3-(4'-fluoro-4-biphenylyl)butylamine; hydrochloride, m.p. 222°-224°.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:37])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:16][CH3:17])[CH:6]=[CH:5][C:4]1=2.[CH2:38]([O:40][C:41]([C:43]1[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=1)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41](=[O:42])[C:43]1[CH:50]=[CH:49][C:46](/[CH:47]=[C:15](/[C:7]2[CH:6]=[CH:5][C:4]3[C:3]([CH3:37])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=3[CH:8]=2)\[CH2:16][CH3:17])=[CH:45][CH:44]=1)[CH3:39]
Reactant: CCC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Product: CCOC(=O)c1ccc(/C=C(\CC)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propyl]-triphenylphosphonium bromide and 4-ethoxycarbonyl-benzaldehyde there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-butenyl]-benzoic acid ethyl ester of melting point 82°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:34]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:34])[N:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:24][CH:25]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CO
Product: CN1CCN(Cc2ccc(Nc3nccc(-c4cnn(C)c4-c4ccc(Cl)cc4)n3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 54 starting from {4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl)}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine (Example 32) and methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([SH:25])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[S:25][C:17]2[CH:16]=[C:15]([O:14][CH3:13])[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: COc1cc(S)cc(OC)c1OC
Product: COc1ccc(C(=O)Sc2cc(OC)c(OC)c(OC)c2)cc1N
Yield: 47 %

Procedure:
Using 3-amino-4-methoxybenzoic acid and 3,4,5-trimethoxyphenylmercaptan as materials, compound 5 is synthesized following a similar method as in Example 28. Yield: 47%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:27][CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1CNC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC2)cn1
Yield: 28 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using azetidine instead of methylamine, to the title compound (32 mg, 28%) which was obtained as a light yellow oil. MS: m/e=350.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13](=O)[C:14](=O)[N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1.B.C1COCC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([CH:13]=[CH:14][N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1
Reactant: COc1cc2c3c(c1)C(=O)C(=O)N3CCC2
Agent: B
Solvent: C1CCOC1
Product: COc1cc2c3c(ccn3CCC2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 50.3 %

Procedure:
8-Methoxy-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (3.0 g, 13.8 mmol), was added to BH3-THF (1.0 M, 30 mL, 30 mmol) dropwise at 0° C. After addition the reaction mixture was stirred 0° C. for 5 h, then warmed to room temperature and stirred for 12 h. The reaction was quenched by adding 5N HCl cautiously at 0° C. at until no gas evolution to pH=8. The reaction mixture was diluted with water, extracted with ether, the combined organic layers were washed with brine, dried over Na2SO4. The solvate was removed in vacuo and purified by flash chromatography using hexanes/ethyl acetate (9:1). After purification, 1.3 g (50%) of title compound was obtained: 1H NMR (300 MHz, CDCl3) 2.21-2.27 (m, 2H), 2.96 (t, 2H, J=6.1 Hz), 3.83 (s, 3H), 4.13 (t, 2H, J=5.8 Hz), 6.36 (d, 1H, J=2.8 Hz), 6.62 (d, 1H, J=1.4 Hz), 6.91 (d, 1H, J=2.2 Hz), 7.05 (d, 1H, J=2.7 Hz).
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH:9]([O:8][CH2:7][CH:6]=[O:13])[C:10]([OH:12])=[O:11]
Reactant: O=C1COCC(=O)O1
Reactant: NCCCCCO
Agent: CS(=O)(=O)[O-]
Product: O=CCOC(NCCCCCO)C(=O)O

Procedure:
methanesulfonate by the following sequence of steps: (a) by reacting diglycolic anhydride and 5-aminopentanol to produce [2-(5-hydroxypentyl)amino-2-oxoethoxylacetic acid, (b) heating to cyclize the latter to obtain 4-(5-hydroxypentyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 5-(3,5-dioxomorpholino)pentyl methanesulfonate and (d) reacting the mesylate with 2-benzhydrylpiperidine.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:55][CH2:56][CH2:57][N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:55][CH2:56][CH2:57][N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: ClCCCN1CCOCC1
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(CCCN3CCOCC3)c2c1
Temperature: 90 °C
Yield: 80.6 %

Procedure:
A mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.139 mmol), 4-(3-chloropropyl)morpholine (27 mg, 0.166 mmol) and K2CO3 (58 mg, 0.417 mmol) in dry DMF (20 mL) was heated to 90° C. for 3 hours. Product was extracted with ethyl acetate (100 mL), organic phase washed with water (3×10 mL) and brine (2×10 mL), then dried over Na2SO4, filtered and concentrated to afford N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (95 mg, crude) as a yellow oil. LCMS: (M+H)+=848.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:47])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)=[CH:35][C:34]=3[CH3:46])[N:27]=2)[CH:12]=1.[CH:48]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH2:49]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:47])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:45][CH2:44][N:43]([CH2:49][CH2:48][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:42][CH2:41]4)=[CH:35][C:34]=3[CH3:46])[N:27]=2)[CH:12]=1
Reactant: Cc1cc(OC2CCNCC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Reactant: C=CS(C)(=O)=O
Solvent: C1CCOC1
Product: Cc1cc(OC2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
To N-(2,6-difluorophenyl)-3-[3-(2-{[2-methyl-4-(4-piperidinyloxy)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide (Example 6) (0.10 g, 0.16 mmol) in THF (5 mL) was added methyl vinyl sulfone (0.028 mL, 0.32 mmol) in one portion. The reaction was stirred at rt until complete by MS. Purification by flash chromatography provided the title compound (0.048 g, 0.065 mmol, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.66 (m, 2H), 1.89-1.97 (m, 2H), 2.19 (s, 3H), 2.22-2.33 (m, 2H), 2.68-2.77 (m, 4H), 3.02 (s, 3H), 3.23-3.28 (m, 2H), 4.34-4.39 (m, 1H), 6.45 (d, J=4.9 Hz, 1H), 6.76-6.85 (m, 1H), 6.88 (s, 2H), 7.22 (dt, J=16.3, 8.2 Hz, 3H), 7.36-7.48 (m, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.78-7.89 (m, 1H), 8.06 (d, J=7.3 Hz, 1H), 8.18 (d, J=5.1 Hz, 1H), 8.31 (s, 1H), 8.89 (s, 1H), 9.30-9.36 (m, 1H), 10.24 (s, 1H). MS (M+H, ES+) 738.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1Cl.[F:17][C:18]1([F:23])[CH2:22][CH2:21][NH:20][CH2:19]1.Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:20]1[CH2:21][CH2:22][C:18]([F:23])([F:17])[CH2:19]1
Reactant: FC1(F)CCNC1
Reactant: CNc1cc(Cl)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNc1cc(N2CCC(F)(F)C2)c(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from methyl-2-chloro-4-methylamino-5-nitro-benzoate (1.00 g, 4.09 mmol), 3,3-difluoro-pyrrolidine×HCl (880 mg, 6.13 mmol), DIPEA (2.8 mL, 16 mmol) and dioxane (10 mL).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: Nc1cc(F)ccc1S
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2ccc(F)cc2N)cc1
Yield: 93.9 %

Procedure:
Following General Procedure A, the title compound (873 mg, 94%) was prepared from 2-amino-4-fluorobenzenethiol (456 mg, 3.19 mmol) and methyl 4-(bromomethyl)benzoate (731 mg, 3.19 mmol), K2CO3 (1.32 g, 9.58 mmol) in DMF (20 ml).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:11]2=3)(=O)=O)C=CC=CC=1.S1C2NC3C(C=2C=C1C(OC)=O)=CC=CC=3.[H-].[Na+].[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:44]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:11]1=2)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2s1
Agent: COC(=O)c1cc2c([nH]c3ccccc32)s1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2c3ccccc3n(C(=O)c3ccccc3)c2s1

Procedure:
Prepared analogously to (20) from (19) (0.5 g), 0.06 g NaH and 0.46 g benzoyl chloride afforded (0.7 g)(21), m.p. 149.5°-151.2° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]=[CH:11]2.ClC1C=CC=C(C(OO)=[O:24])C=1>C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]1[O:24][CH:11]12
Reactant: Brc1cccc2c1CC=C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: Brc1cccc2c1C=C1OC12
Reaction time: 4 h
Yield: 38.4 %

Procedure:
250 ml of pH 8 phosphate buffer, 150 ml of methylene chloride, 200 mg of tetrabutylammonium hydrogenosulphate and 10 g of 4-bromo-3H-indene are mixed together. At 0° C. 10 g of metachloroperbenzoic acid is added in several lots, then the temperature of the mixture is allowed to rise to the ambient over 4 hours, 10 g of metachloroperbenzoic acid is added at 0° C. and the temperature is allowed to rise to 20° C. over 2 hours. 3 g of metachloroperbenzoic acid is added and the mixture is left for 16 hours at ambient temperature, then decanted and extracted with methylene chloride; the extracts are washed with water, with a thiosulphate solution and with water, dried and evaporated to dryness. The residue is chromatographed on silica, eluting with a mixture of hexane and isopropyl ether (9-1) with 3% of triethylamine, and 4.11 g of expected product is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][N:18]([CH3:23])[C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cc[nH]c(=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 59.5 %

Procedure:
To a solution of 85 mg (0.274 mmol) of 4-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-1H-pyridin-2-one in 6 ml of DME were added 76 mg (0.55 mmol) of potassium carbonate and 0.034 ml (0.55 mol) of methyl iodide. The suspension was stirred at room temperature for 30 h. The mixture was diluted with 20 ml of ethyl acetate, filtered and concentrated in vaccuo. After purification by flash chromatography on silicagel one obtains 53 mg (0.163 mmol, 60%) of the title compound, as a crystalline yellow solid, MS: m/e=324.2, 326.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[C:31]([CH3:33])([CH3:32])[N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[C:31]([CH3:32])([CH3:33])[N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:10](=[O:14])[CH2:9]2)=[CH:15][CH:16]=1
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Reactant: Cn1c2c(c3ccc(Br)cc31)C(C)(C)N(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)C(C)(C)N(C(=O)OC(C)(C)C)CC2
Yield: 66.1 %

Procedure:
A suspension of 4-(4-fluorophenethyl)piperazin-2-one (66.6 mg, 0.300 mmol), tert-butyl 7-bromo-1,1,5-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (120 mg, 0.300 mmol), CuI (114 mg, 0.600 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (95.0 μL, 0.600 mmol) and Cs2CO3 (195 mg, 0.600 mmol) in dioxane (5.00 mL) was degassed under reduced pressure for 5 min. The suspension was put under N2 and stirred at refluxing temperature for 24 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH was added, and the resulting suspension was stirred at 25° C. for 20 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine (3×). The resulting solution was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 50:50) afforded the title compound (106 mg, 66%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J=8.5 Hz, 1H), 7.21-7.17 (m, 3H), 7.02-6.95 (m, 3H), 3.85 (t, J=5.0 Hz, 2H), 3.75 (t, J=5.0 Hz, 2H), 3.60 (s, 3H), 3.43 (s, 2H), 2.91-2.88 (m, 2H), 2.86-2.82 (m, 2H), 2.78-2.70 (m, 4H), 1.85 (s, 6H), 1.55-1.53 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][C:22]=1[F:31].CCN(C(C)C)C(C)C.O1CCOCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[F:10][C:4]1[CH:5]=[C:6]([S:8][CH3:9])[CH:7]=[C:2]([F:1])[C:3]=1[C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][C:22]=1[F:31]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CSc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(SC)cc2F)n1
Temperature: 120 °C
Yield: 40.4 %

Procedure:
In a sealed tube, a mixture of 2-[2,6-difluoro-4-(methylthio)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 3.49 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (1.23 g, 5.24 mmol) and DIPEA (1.83 mL, 10.5 mmol) in a mixed solvent of 1,4-dioxane (15 mL) and water (0.51 mL) was stirred and flushed with nitrogen bubbles for 5 min. before bis(tri-tert-butylphosphine)palladium (360 mg, 0.70 mmol) was added. The reaction mixture was heated at 120° C. for 30 min. After cooling, the reaction mixture was filtered, and the filter was washed with THF. The filtrate was concentrated and then purified by silica gel column chromatography using CombiFlash® (0 to 20% EtOAc in hexanes) to give the sub-title compound as powder (442 mg, 40%). LCMS calc. for C14H11F3NO2S (M+H)+: m/z=314.1. Found: 314.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: CN
Product: CNc1ccc2c([N+](=O)[O-])cccc2n1

Procedure:
1.0 g (4.8 mmol) of 2-chloro-5-nitroquinoline and 20 ml of 2 M methanolic methylamine solution are heated in a pressure vessel for 8 hours to 120° C. The batch is concentrated by evaporation after the addition of toluene. The residue is purified by column chromatography on silica gel with hexane-ethyl acetate: 580 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CN2CCOCC2)cc1

Procedure:
4-Methyoxybenzylchloride (25 g, 0.16 mol), morpholine (14 g, 0.16 mol), and potassium carbonate (22 g, 0.16 mol) were taken up in acetonitrile and Kl (8.7 g, 0.04 mol) added. The reaction mixture was heated at reflux for 18 h, filtered, and the filtrate concentrated and azeotropped with benzene to give 17.5 g (88%) as an oil; IR(film, υ=cm−1) 2956, 2806, 1514, 1246, 1118, 866; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (4H, br. s), 3.35 (2H, s), 3.53 (4H, t, J=4.4 Hz), 3.71 (3H, s), 6.86 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz); MS(DCl)m/z: 208 (MH+).
Reaction SMILES: [Li+].[B-](CC)(CC)CC.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:40][CH:41]([CH3:43])[CH3:42])[S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:31](=[O:39])[CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:25]([CH:30]=2)[C:26](OC)=[O:27])(=[O:20])=[O:19])=[CH:13][CH:12]=1)[CH3:10].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:40][CH:41]([CH3:42])[CH3:43])[S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH:31]([OH:39])[CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:25]([CH2:26][OH:27])[CH:30]=2)(=[O:19])=[O:20])=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(=O)CN3CCOCC3)c(C(=O)OC)c2)cc1
Agent: CC[B-](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CN3CCOCC3)c(CO)c2)cc1
Reaction time: 16 h

Procedure:
A solution of Super-Hydride® (1 M in tetrahydrofuran, 0.388 mL, 0.388 mmol) was added slowly to a solution of methyl 5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2-(2-morpholinoacetyl)benzoate (65 mg, 0.129 mmol) in tetrahydrofuran (THF) (0.5 mL) at room temperature, under nitrogen. The solution was stirred for 16 hours, then treated with HCl (2 N, 2 mL) and stirred for 10 minutes. The mixture was basified with sodium bicarbonate solution and extracted with ethyl acetate (2×5 mL). The organics were dried (MgSO4) then evaporated and purification of the crude attempted on a silica (Si) cartridge eluting with 5% methanol-dichloromethane+0.5% ammonia, although this gave poor separation. Purification was successfully achieved using a silica (Si) cartridge eluting with 1-3% methanol-dichloromethane+0.1-0.3% ammonia to give the desired product as a cream solid, 31 mg. LCMS [LCMS1] Rt 0.90 min, m/z (ES+) 477 (M+H).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([F:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>ClCCl>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:24](=[O:25])[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.2 %

Procedure:
A mixture of 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-amine (528 mg, 2.37 mmol), potassium carbonate (979 mg, 7.10 mmol) and phenyl chloroformate (556 mg, 3.55 mmol) in anhydrous dichloromethane (20 mL) was stirred at rt for 15 h. Additional phenyl chloroformate (556 mg, 3.55 mmol) and potassium carbonate (979 mg, 7.10 mmol) was added and the mixture stirred for a further 4 h. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water, saturated aqueous sodium hydrogen carbonate solution, then dried over magnesium sulfate and filtered. Concentration under reduced pressure gave an oil which was purified via silica gel column chromatography (eluting with a gradient of 12% ethyl acetate in hexanes to 100% ethyl acetate) to afford phenyl 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (400 mg, 49%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.51-7.58 (m, 5H), 7.35-7.41 (m, 2H), 7.26 (m, 1H), 7.15 (m, 2H), 7.00 (brs, 1H), 6.80 (s, 1H), 2.04 (t, J=18 Hz, 3H); LC-MS (ESI) m/z 344 (M+H)+.