Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]=O)[CH:9]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CC(O)=O.[BH3-]C#N.[Na+]>CCO>[O:42]1[CH2:43][CH2:44][N:39]([CH2:27][C:10]2[CH:9]=[C:8]([N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:37])[CH3:38])[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[N:13]3[N:14]=[CH:15][C:16]([C:17]4[CH:18]=[N:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[C:12]3[N:11]=2)[CH2:40][CH2:41]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(CN2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.4 %

Procedure:
To 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde (0.15 g, 0.3 mmol) in EtOH (10 mL) was added morpholine (0.12 mL, 1.4 mmol) and AcOH (0.2 mL), and the resulting mixture was stirred at room temperature for 15 minutes. NaBH3CN (0.12 g, 2.0 mmol) in EtOH (1.5 mL total) was then added and the reaction mixture was stirred at room temperature for 16 hours, at which time LC/MS analysis confirmed full consumption of starting material. Saturated NaHCO3 solution (˜20 mL) was added and the mixture was stirred for 30 minutes. The mixture was transferred to a separatory funnel with CH2Cl2 (30 mL) and H2O (10 mL) and brine (20 mL) was then added. Organics were extracted with CH2Cl2 (4×30 mL), dried (Na2SO4) and concentrated in vacuo to give crude 5-(morpholinomethyl)-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine as a brown oil (0.2 g). LCMS: 2.01 mins, m/z=621.3 (MH+).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[C:22](I)=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=1.ClC1C=C([I:35])C(C(F)(F)F)=CN=1>C1COCC1.II>[Cl:16][C:17]1[N:18]=[C:19]([I:35])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1cnc(Cl)c(I)c1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Agent: CC1(C)CCCC(C)(C)N1
Agent: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Cl)nc1I
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (4.277 g, 5.110 mL, 30.28 mmol) in THF (18.00 mL) cooled to −78° C. was added nBuLi in hexanes (11.72 mL of 2.5 M, 29.30 mmol). The solution was allowed to warm up to 0° C. and was stirred for 15 minutes at that temperature before cooling it again to −78° C. Iodine (12.40 mg, 2.515 μL, 0.04884 mmol) was added followed by a dropwise addition of a solution containing a mixture of 2-chloro-3-iodo-5-(trifluoromethyl)pyridine (2 g, 6.505 mmol) and 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (4.000 g, 13.01 mmol) in THF (18.00 mL). The solution was stirred at −78° C. for 2 hours. The reaction mixture was partitioned between a 1M solution of HCl and ether. The organic extract was washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a pale yellow oil (1.92 g, 32% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[C:12]([CH3:22])=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:15]=1.O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[C:12]([CH3:22])=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:15]=1)[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CO)ccc1OCc1cn(-c2ccccn2)nc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1cn(-c2ccccn2)nc1C
Reaction time: 15 h
Yield: 31.5 %

Procedure:
To a mixture of {3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]phenyl}methanol (0.73 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.45 g), tributylphosphine (0.67 g) and tetrahydrofuran (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.83 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as pale-yellow crystals (0.35 g, yield 32%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 179-180° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>C(Cl)Cl.CO>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N:7][C:2]([NH:36][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:38][CH:37]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCCC4)n3)cc2)CC1
Yield: 50 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2,5-dichloro-N-(2-(pyrrolidin-1-ylsulfonyl)phenyl)pyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 50% yield (yellow solid) after flash chromatography eluent (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 8.61 (d, 1H, J=8.2 Hz), 8.18 (s, 1H), 7.96 (d, 1H, J=7.9 Hz), 7.58 (t, 1H, J=7.7 Hz), 7.51 (d, 2H, J=8.2 Hz), 7.30 (d, 2H, J=8.2 Hz), 7.26 (m, 1H), 3.53 (s, 2H), 3.30 (m, 4H), 2.53 (bs, 8H), 2.34 (s, 3H), 1.84 (m, 4H); MS (ESI): 542.20 [M+H]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:14]1[C:13](=[C:22]3[C:17](=[CH:16][CH:15]=1)[CH:18]=[CH:19][CH:20]=[N:21]3)[NH:12][S:9]2(=[O:10])=[O:11]
Reactant: Cc1ccc(N)c(S(=O)(=O)Nc2cccc3cccnc23)c1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)S(=O)(=O)Nc1c-2ccc2cccnc12
Yield: 13.2 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-5-methyl-N-quinolin-8-yl-benzenesulfonamide (Intermediate 296) (160 mg, 0.51 mmol), t-butyl nitrite (80 mg, 0.76 mmol), AcOH (1.6 ml) and THF (1.6 ml) gave the title compound (20 mg, 13%) after purification by column chromatography with n-hexane/DCM (1:1) as the eluent.
Reaction SMILES: Cl[C:2]([F:9])([F:8])C(OCC)=O.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH:2]([F:9])[F:8])=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
Ethyl chlorodifluoroacetate (25 mL, 0.20 mol) was added to 4-(benzyloxy)phenol (20.10 g, 0.10 mol), and potassium carbonate (41.90 g, 0.30 mol) in dimethylformamide (200 mL) and the mixture was stirred at 80° C. for 18 h. Additional ethyl chlorodifluoroacetate (12.7 mL, 0.10 mol) and potassium carbonate (27.74 g, 0.20 mol) were added and the mixture was stirred at 80° C. for 6 h. Additional ethyl chlorodifluoroacetate (12.7 mL, 0.10 mol) and potassium carbonate (27.74 g, 0.20 mol) were added and the mixture was stirred at 120° C. for 15 h. The mixture was cooled, poured into water (1000 mL) and extracted with ethyl acetate (500 mL). The organic fraction was washed with aqueous sodium hydroxide (1M, 500 mL) and brine (500 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/CH2Cl2 (90:10) to give the title compound as a colorless solid (6.67 g, 27%). 1H NMR (360 MHz, CDCl3) δ 5.05 (2H, s), 6.42 (1H, t, J 74 Hz), 6.94 (2H, m) 7.06 (2H, m), and 7.31-7.44 (5H, m).
Reaction SMILES: [CH2:1]([C@H:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@@H:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](I)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](/[CH:3]=[CH:2]/[CH2:1][C@H:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@@H:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Ic1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](C/C=C/c1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a stirred solution of di-tert-butyl (4S)-4-allyl-N-(tert-butoxycarbonyl)-L-glutamate (345 mg, 0.86 mmol) in acetonitrile (5 ml) at room temperature was slowly added 1-(benzyloxy)-4-iodobenzene (ABCR GmbH & CO. KG) (321 mg, 1.04 mmol) in 3 ml acetonitrile, triethylamine (144 μl, 1.04 mmol) in 3 ml acetonitrile, and palladium(II) acetate (Aldrich) (39 mg, 0.17 mmol). The mixture was heated in a pressure tube at 80° C. for 2 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The crude material was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH2:7]([O:11][CH3:12])[CH:8]1[O:10][CH2:9]1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][CH:8]([OH:10])[CH2:7][O:11][CH3:12])[CH:6]=1
Reactant: COCC1CO1
Reactant: Brc1cn[nH]c1
Product: COCC(O)Cn1cc(Br)cn1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A solution of 4-bromopyrazole (200 mg, 1.36 mmol) in methyl glycidyl ether (510 mg, 5.79 mmol) was heated at 100° C. for 70 minutes. After cooling to r.t., the excess methyl glycidyl ether was removed in vacuo to give the title compound (165 mg, 52%) as a clear yellow liquid. δH (CDCl3) 3.21-3.24 (1H, m), 3.31-3.35 (2H, m), 3.38 (3H, s), 4.08-4.30 (3H, m), 7.47-7.50 (2H, m). LCMS (ES+) 235, 237 (M+H)+.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[I:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([I:20])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: Nc1ccc(I)c(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cc1ccc(-n2cnc3cccnc32)cc1)Nc1ccc(I)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-iodo-3-trifluoromethyl-phenylamine. Title compound: ES-MS: 522.7 [M+H]+; single peak at tR=4.72 min (System 1); Rf=0.25 (CH2Cl2/MeOH, 95:5).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>ClCCl>[Br:32][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: COCc1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1cccc(CBr)n1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of 6-methoxymethyl-2-pyridinemethanol (860 mg, 5.64 mmol) and triphenylphosphine (1.78 g, 6.77 mmol) in dichloromethane (40 mL) at 0° C. was treated portionwise with CBr4 (2.80 g, 8.43 mmol), stirred for 1 h, concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:1)] to give the title compound (1.20 g, 99%) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.71 (1H, t, J 8.0 Hz), 7.35 (2H, d, J 8.0 Hz), 4.58 (2H, s) and 4.54 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.O=[C:18]([CH3:37])[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([CH3:37])[C:19]([C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH2:34])=[O:33])=[CH:35][CH:36]=3)[CH2:24][CH2:23]1)=[O:21])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)N1CCC(c2ccc(C(N)=O)cc2)CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)N1CCC(c2ccc(C(N)=O)cc2)CC1
Temperature: 82 °C
Yield: 75.8 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)(phenyl)methanone (693 mg, 3.0 mmol) in ethanol (10 ml) was added 4-(1-(3-oxobutanoyl)piperidin-4-yl)benzamide (893 mg, 3.1 mmol) followed by ytterbium triflate (186 mg, 0.3 mmol). The mixture was heated at 82° C. for 12 hours. The reaction mixture was cooled to room temperature, and the white powder thus obtained was filtered off, washed with ethanol, ethyl acetate, and finally ether to provide 4-(1-(6-chloro-2-methyl-4-phenylquinoline-3-carbonyl)piperidin-4-yl)benzamide (1.1 g, 76%) as a free flowing white powder. 1H NMR (DMSO-d6, 400 MHz) δ: 1 Rotameric forms complicates spectrum, the major rotamer is described; δ 8.09 (d, 1H, J=8.9 Hz); 7.9 (bs, NH, 1H); 7.8 (m, 3H); 7.7-7.5 (m, 6H); 7.25 (bs, NH, 1H); 6.8 (app d, 2H); 4.5 (d, 1H, J=12.9 Hz); 3.4-3.3 (m, 1H); 3.38 (s, 3H); 3.13 (app t, 1H, J=12.9 Hz); 2.8-2.4 (m, 2H); 2.5 (s, 3H); 0.72 (m, 1H); 0.54 (m, 1H). LC MS (CI) shows M+H 484.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].O.C(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: O
Product: NS(=O)(=O)Oc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 10.1 %

Procedure:
In one portion, 96 g (0.75 mole) of 4-chlorophenol was added to a stirred solution of 67.5 ml (0.75 mole) of chlorosulfonylisocyanate in 400 ml of toluene. The solution was heated at 100° C. for 16 hr and the solution chilled with an ice-acetone bath and water added dropwise until evolution of carbon dioxide ceased. The tan solid which precipitated from solution was collected and dried for 16 hr to yield 133.4 g. A 25 g portion was recrystallized from 100 ml of toluene to give 15.8 g of white solid, mp 103°-104° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13][CH:14]1[CH:19]=[C:18]([CH3:20])[CH:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[O:16][NH:15]1>C(#N)C.C(Cl)(Cl)Cl>[CH3:13][CH:14]1[CH:19]=[C:18]([CH3:20])[CH:17]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[O:16][N:15]1[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)(=[O:10])=[O:9]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C2ONC(C)C=C2C)cc1
Agent: Cl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2ON(S(=O)(=O)c3cccc(C)c3)C(C)C=C2C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-methylbenzenesulphonyl chloride (0.075 mmol) in acetonitrile (1.5 ml) was added a solution of 3,6-dihydro-3,5-dimethyl-6-(4-methoxyphenyl)-2H-1,2-oxazine hydrochloride(0.403 mmol) in chloroform (0.5 ml) followed by poly(4-vinyl)pyridine (53 mg). The mixture was shaken at room temperature for 24 h then added polystyrene (co-divinylbenzene)amino methylated (100 mg) and the mixture shaken at room temperature for a further 24 h. The mixture was then filtered and the resin washed twice with chloroform. The filtrate was evaporated to give 3,6-dihydro-3,5-dimethyl-6-(4-methoxyphenyl)-2-(3-methylbenzenesulphonyl)-2H-1,2-oxazine as an oil. 1H NMR (CDCl3)δ 1.56(3H, d), 2.39(3H, s), 3.82(3H, s) 4.49(1H, m), 5.20(1H, s), 5.69(1H, d), 6.81(2H, d), 7.11(2H, d), 7.34(2H, m), 7.67(2H, d)
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=O)C.C1COCC1.CC(C[AlH]CC(C)C)C>C(OCC)C>[C:11]([C:9]1[CH:10]=[C:6]([CH2:4][OH:3])[N:7]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:8]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(C)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To an oven dried round bottom flask containing 5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.64 g, 2.2 mmol) was added anhydrous THF (20 mL) followed by the drop wise addition of DIBAL-H (0.96 mL, 4.9 mmol) under nitrogen. After stirring at room temperature for 30 minutes the reaction was diluted with 100 mL diethyl ether and quenched with 5 mL Methanol stirring for an additional 30 minutes at room temperature. The resulting slurry was treated with 5 g MgSO4 and filtered through a pad of diatomaceous earth. The filter cake was washed with 3×75 mL portions of ether and the combined filtrates concentrated under vacuo to afford the desired alcohol as a clear oil (0.515 g, 96%). No further purification was necessary. Expected mass=244. Observed mass=245.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Br[CH2:8][C:9]#[N:10]>C1COCC1>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:8][C:9]#[N:10])[CH2:3]1
Reactant: N#CCBr
Reactant: OC1CCNC1
Solvent: C1CCOC1
Product: N#CCN1CCC(O)C1
Yield: 64545.7 %

Procedure:
The method follows that of S3 using 3-hydroxypyrrolidine (15 g, 0.172 mol), BrCH2CN (22.67 g, 0.189 mmol) and dry THF (60 mL). The title-compound was yielded as a straw-coloured oil (15.39 g, 71%) after flash chromatography using CH2Cl2/CH3OH (9:1) as eluent. δH (250 MHz; CDCl3); 1.9-2.25 (m, 2H, 2×ring-H), 2.3 (m, 1H, ring-H), 2.65 (d, OH), 2.85-3.05 (m, 3H, 3×ring-H), 3.95 (d, 2H, NCH2CN) and 4.2 (m, 1H, CH2CHOH); FAB MS, m/z (M+H)+ 127.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:20]4[S:21][C:22]([Cl:25])=[CH:23][CH:24]=4)O)[CH:16]=3)[N:11]([CH3:26])[C:10](=[O:27])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:30])=O>C(Cl)Cl>[Cl:30][CH:18]([C:20]1[S:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:26])[C:10](=[O:27])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(O)c3ccc(Cl)s3)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(Cl)c3ccc(Cl)s3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(3-chloro-phenyl)-6-[(5-chloro-thiophen-2-yl)-hydroxy-methyl]-1-methyl-1H-quinolin-2-one 49 mg, 0.12 mmol) in CH2Cl2 (0.5 ml) was added thionyl chloride dropwise. The reaction mixture was stirred at room temperature for four hours. Thionyl chloride was removed under reduced pressure. The crude chloride was taken up in toluene and concentrated under vacuum to give a yellow solid which was used without further purification.
Reaction SMILES: NC1C=CC=CC=1C([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=O.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+]>CC(O)(C)C>[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:21])([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccccc1[N+](=O)[O-]

Procedure:
t-Butyl 2-aminobenzoate ##STR103## A mixture of 2-nitrobenzoyl chloride (15 mL, 110 mmol) and t-BuOH (100 mL) were heated at reflux for 3 h. The cooled mixture was poured onto ice-water, basified with Na2CO3 and extracted with CH2Cl2 (×2). The combined organic extracts were washed with brine, the solvents evaporated in vacuo and the residue was purified by column chromatography upon silica gel using hexanes-EtOAc (95:5) as eluant to give t-butyl 2-nitrobenzoate (4.9 g, 22 mmol) as a yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].S(=O)(=O)(O)O.[Br:23]N1C(=O)CCC1=O>>[Br:23][C:14]1[CH:15]=[C:16]([Cl:17])[C:9]([Cl:8])=[C:10]([CH:13]=1)[CH:11]=[O:12]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cc(Br)cc(Cl)c1Cl
Reaction time: 3 h

Procedure:
To a TFA solution (0.38 M) of 2,3-dichlorobenzaldehyde (1 eq.) was added sulfuric acid (5 eq.). Over a period of 3 h, N-bromosuccinimide (1.5 eq.) was added portionwise at RT to afford, in the end, a yellow-orange solution. After 72 h, the crude reaction mixture was diluted with 9:1 (v/v) hexanes:ether and then washed sequentially with water, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
279.0 g of wet crystals of L-Phe 1/2 sulfate hemihydrate (20% of adsorbed water based on the total weight, 1.00 mole as L-Phe) was suspended in 250 ml of MeOH and, after adding 60 ml of 98% sulfuric acid, reacted at 85° C. for 4 hours. The reaction was carried out while distilling off the water and MeOH and replenishing the MeOH.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)[CH:3]=1
Reactant: Brc1cc(I)cc2nnsc12
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cccc(-c2cc(Br)c3snnc3c2)c1
Yield: 82.8 %

Procedure:
A mixture of 7-bromo-5-iodo-1,2,3-benzothiadiazole (20 mg, 0.0586 mmol), 3-fluorophenylboronic acid (9.85 mg, 0.0704 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane complex (2.14 mg, 0.00293 mmol), potassium carbonate (24.3 mg, 0.176 mmol) and 4:1 1,4-dioxane:water (3 mL) was heated to 60° C. for 2 h. The solution was concentrated. Purification by ISCO chromatography (1 to 3% EtOAc:heptane) afforded 15 mg (83%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.13-7.21 (m, 1 H), 7.39 (dt, J=9.7, 2.0 Hz, 1 H), 7.45-7.55 (m, 2 H), 8.04 (d, J=1.5 Hz, 1 H), 8.74 (d, J=1.3 Hz, 1 H).