Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)cc4Cl)c3c2s1
Yield: 32 %

Procedure:
Prepared from VII and 2,4-dichloroaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 32%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3063, 2231, 1736, 1644, 1611, 1577, 1459, 1380, 1355, 1310, 1242, 1173, 1098, 1051, 983, 830, 818; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, 1H, J=9.0 Hz), 8.21 (s, 1H), 7.80 (d, 1H, J=9.0 Hz), 7.63 (s, 1H), 7.39 (d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=8.1 Hz); HRMS calcd for C16H8N5SCl2 (M+H+): 371.9877, found 371.9877.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]([C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14]2[C:15](=[O:45])[N:16]([CH3:44])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[N:35]=[CH:34][C:33]5[C:28](=[C:29]([F:40])[CH:30]=[C:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:32]=5)[C:27]4=[O:41])[C:21]=3[CH2:42][OH:43])[CH:19]=2)=[CH:11][CH:12]=1)([CH3:6])[CH3:5].[H-].[OH-].[Li+]>O1CCOCC1.O>[C:36]([C:31]1[CH:32]=[C:33]2[C:28](=[C:29]([F:40])[CH:30]=1)[C:27](=[O:41])[N:26]([C:22]1[C:21]([CH2:42][OH:43])=[C:20]([C:18]3[CH:19]=[C:14]([NH:13][C:10]4[N:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:46])=[O:2])=[CH:12][CH:11]=4)[C:15](=[O:45])[N:16]([CH3:44])[CH:17]=3)[CH:25]=[CH:24][CH:23]=1)[N:35]=[CH:34]2)([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)C(C)(C)c1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)C(=O)O)cn2)c1=O
Temperature: 25 °C
Yield: 85.7 %

Procedure:
2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid methyl ester (390 mg, 0.62 mmol) was dissolved in dioxane (5 ml). Lithium hydroxide monohydride (78 mg, 1.86 mmol) was dissolved in 5 ml of water and added dropwise. The reaction was heated at 50 degrees centigrade for three hours. The reaction mixture was concentrated, ethyl acetate was added and the layers were separated. The aqueous layer was acidified with 1 M HCL. Ethyl acetate was added and the layers were separated. The organic layer was dried and concentrated. Isopropyl acetate was added to the residue and the mixture was heated to form a solution which was cooled to room temperature and allowed to stand at room temperature for several hours. The amorphous solid was filtered and dried to give 325 mg (86%) of 2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid. A portion of this material was recrystallized from acetonitrile to provide a crystalline solid. MS: (M+H)+=612; MP=218.0-220.0° C. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H) 1.46 (s, 6 H) 3.17 (d, J=4.91 Hz, 1 H) 3.60 (s, 3 H) 4.27-4.42 (m, 2 H) 4.57-4.66 (m, 1 H) 7.26 (d, J=8.69 Hz, 1 H) 7.33-7.45 (m, 3 H) 7.54 (s, 2 H) 7.75 (d, J=13.22 Hz, 1 H) 7.87 (s, 1H) 8.18 (d, J=2.27 Hz, 1 H) 8.51 (d, J=2.64 Hz, 1 H) 8.60 (s, 1 H) 8.65 (d, J=1.89 Hz, 1H) 12.35 (br s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)nc1
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a solution of 6-chloronicotinic acid (20.0 g, 0.127 mol) in CH2Cl2 (250 mL) was added oxalyl chloride (123.3 mL, 0.15 mol) with 1-5 drops of DMF. The solution was stirred 18 h and concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and cooled in an ice bath. To this was added MeOH (20 mL) and the solution was stirred for 15 min while maintaining a temp below 40° C. The solvent was removed in vacuo, and the residue was dissolved in Et2O, washed with H2O and brine, dried with Na2SO4, and filtered through SiO2. The solvent was removed in vacuo to yield 6-chloronicotinic acid, methyl ester (21 g) as an off-white solid: 1H-NMR (300 MHz, CDCl3) δ 9.02 (d, J=13.8 Hz, 1H), 8.51-8.06 (m, 1H), 7.76-7.30 (m, 1H), 4.01 (s, 3H); EIMS m/z 171 ([M]+), which was used in Step 2 without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][NH:1]2)[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)cccc1F
Reactant: OC[C@H]1CCCN1
Product: N#Cc1c(N)cccc1OC[C@H]1CCCN1

Procedure:
Prepared as in Example 24d from (R)-pyrrolidin-2-ylmethanol and 2-amino-6-fluorobenzonitrile as brown solid (57%). MS 218 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)C(CCCN3CCC(C4C=C(NC(=O)C(C)C)C=CC=4)CC3)=C2C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:45](OC)[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[C:56]([NH:60][C:61](=[O:65])[CH:62]([CH3:64])[CH3:63])[CH:57]=[CH:58][CH:59]=2)[CH2:50][CH2:49]1.Cl.C1(N(C2C=CC=CC=2)N)C=CC=CC=1>>[CH3:63][CH:62]([CH3:64])[C:61]([NH:60][C:56]1[CH:57]=[CH:58][CH:59]=[C:54]([CH:51]2[CH2:52][CH2:53][N:48]([CH2:47][C:46]3[C:2]4[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:7]([C:15]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:45]=3)[CH2:49][CH2:50]2)[CH:55]=1)=[O:65]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Reactant: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)OC
Agent: Cl
Agent: NN(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cn(-c4ccccc4)c4ccccc34)CC2)c1
Yield: 56 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, N-{3-[1-(3,3-dimethoxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (15.2 mg, 0.0436 mmol) and 1,1-diphenylhydrazine hydrochloride (11.6 mg, 0.0524 mmol) provided 2-methyl-N-(3-{1-[(1-phenyl-1H-indol-3-yl)methyl]-4-piperidinyl}phenyl)propanamide (11 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, 1H, J=7.8 Hz), 7.57 (d, 1H, J=7.7 Hz), 7.54–7.47 (m, 4H), 7.43–7.32 (m, 4H), 7.25–7.16 (m, 4H), 6.95 (d, 1H, J=7.8 Hz), 3.87 (s, 2H), 2.53–2.47 (m, 2H), 2.21 (dt, 2H, J=3.0, 10.5 Hz), 2.12–1.77 (m, 6H), 1.24 (d, 6H, J=6.9 Hz); ESMS m/e: 451.3 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][Br:1])=[CH:30][CH:29]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
N-Bromosuccinimide (19 g, 0.107 mole) and benzoyl peroxide (2.5 g, 0.01 mole) were added to p-chlorotoluene (13 g, 0.103 mole) in carbon tetrachloride (100 mL). The reaction mixture was stirred and refluxed gently for 2 hours. When the succinimide rose to the surface, the reaction was finished. The solution was cooled to room temperature and the succinimide was filtered off. The filtrate was evaporated on a rotary evaporator. Then distillation gave p-chlorobenzyl bromide as colorless crystal (80° C.-85° C./1 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:10]32[O:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[N-:25]=[N+:26]=[N-:27].[Na+].O>CN(C=O)C>[N:25]([CH2:11][C:10]1([OH:12])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[N+:26]=[N-:27]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C2(CO2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(O)(CN=[N+]=[N-])C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of tert-butyl (3RS,4SR)-4-(3,4-dichlorophenyl)-1,5-dioxa-8-azaspiro[2.6]nonane-8-carboxylate (460 mg) in DMF (5 ml) was added sodium azide (240 mg), and the mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (232 mg).
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][CH2:8][CH:9]([OH:12])[CH2:10][F:11].Br[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C.C1COCC1>[F:7][CH2:8][CH:9]([O:12][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:10][F:11]
Reactant: OC(CF)CF
Reactant: O=C(CBr)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(COC(CF)CF)OCc1ccccc1
Reaction time: 0.67 h
Yield: 42.7 %

Procedure:
Sodium tert-butoxide (0.923 g, 9.60 mmol) in DMF (20 mL)/THF (12 mL) mixture was cooled down to 0° C. and set under N2 atmosphere. 1,3-Difluoropropan-2-ol (0.717 mL, 9.25 mmol) was added via syringe and stirred for 40 min then benzyl 2-bromoacetate (1.373 mL, 8.73 mmol) was added dropwise via syringe and the mixture was stirred at rt for 16 hours. Ethyl acetate and sat NaHCO3 solution were added and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude oil was purified by silica gel chromatography (heptane/EtOAc gradient) to afford the title compound (0.91 g, 43% yield).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([Cl:13])[CH:3]=1.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:8](=[O:10])[CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([Br:1])=[CH:3][C:4]=2[Cl:13])[CH:18]=1
Reactant: O=C(O)COc1ccc(Br)cc1Cl
Reactant: COC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(NC(=O)COc2ccc(Br)cc2Cl)c1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To solution of (4-bromo-2-chloro-phenoxyacetic acid (100 mg, 0.378 mmol), 2-amino isonicotinic acid methyl ester (86.42 mg, 0.568 mmol) and DMAP (69.43 mg, 0.568 mmol) in DMF 2 mL was added PyBOP (295 mg, 0.568 mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:9˜4:6) to give 2-[2-(4-bromo-2-chloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.084 g, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:35])[C:33]#[CH:34].C(Cl)Cl>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:34]#[C:33][CH2:32][OH:35])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (264 mg), PdCl2(PPh3)2 (17.3 mg), and CuI (4.7 mg) in 9.6 mL Et2NH is added propargyl alcohol (0.029 mL, 0.492 mmol). Distilled CH2Cl2 (14 mL) is added to help solublize the reactants. The reaction is stirred at room temperature overnight, then condensed to remove the solvents. The crude product is adsorbed onto silica and chromatographed (eluent 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), and 3% MeOH in CH2Cl2 (2L)). Product-containing fractions are combined and condensed to afford 148.2 mg (63%) of the desired product as a tan solid.
Reaction SMILES: [NH2:1][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)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.[Cl:22][C:23]1[N:24]=[N:25][C:26](OC)=[CH:27][CH:28]=1.C(N(CC)CC)C>C(O)CCCC>[NH2:1][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)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:26]3[N:25]=[N:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: COc1ccc(Cl)nn1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CCN(CC)CC
Solvent: CCCCCO
Product: COc1cc2nc(N3CCN(c4ccc(Cl)nn4)CC3)nc(N)c2cc1OC

Procedure:
4-Amino-6,7-dimethoxy-2-piperazinoquinazoline (3.0 g, 10.4 mmole), 3-chloro-6-methoxy-pyridazine (3.96 g, 27.4 mmole) and triethylamine (5.0 g, 49.5 mmole) in n-pentanol (210 ml) were heated under reflux for 25 hours. The solvent was evaporated in vacuo and the residue partitioned between chloroform and saturated aqueous sodium carbonate solution. The organic layer was separated, washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel (200 g) eluting with chloroform followed by 5% methanol in chloroform. Further purification of the major product by HPLC using a Waters 500 Prep. LC/system, eluting with 6% by volume methanol in methylene chloride at a flow rate of 0.15 liters per minute gave the desired product which was recrystallized from methanol, m.p. 269°-270° C. (0.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:23])[C:12]=2[C:13]2[S:22][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>O1CCCC1.C(Cl)Cl>[NH2:21][C:20]1[C:15]2[CH:14]=[C:13]([C:12]3[N:11]([CH3:23])[CH:10]=[N:9][C:8]=3[C:4]3[CH:3]=[C:2]([NH:1][C:32]([NH:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[O:33])[CH:7]=[CH:6][CH:5]=3)[S:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=C=Nc1ccccc1F
Reactant: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cnc(-c2cccc(NC(=O)Nc3ccccc3F)c2)c1-c1cc2c(N)ncnc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
6-[4-(3-Aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (64 mg) in anhydrous tetrahydrofuran (10 mL) was added to 2-fluorophenyl isocyanate (34 mg) and stirred under an inert atmosphere at ambient temperature for 1 hr. The mixture was diluted with DCM (5 mL) then purified by chromatography on silica eluting with a gradient of 0-50% EtOAc/DCM, then 0-50% MeOH (containing 1% concentrated aqueous amnmonia)/DCM to give the title compound as a solid (76 mg, 82%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([OH:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:16][C@@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[CH2:15][CH2:14]1)(=[O:27])=[O:26]
Reactant: O[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-ol (1.476 g, 6.79 mmol) from Step B and triethylamine (1.420 mL, 10.19 mmol) were combined in dichloromethane (30 mL). Methanesulfonyl chloride (0.635 mL, 8.15 mmol) was added as a solution in 20 mL of dichloromethane dropwise via addition funnel. The reaction was stirred at room temperature for 30 minutes and concentrated. The crude material was absorbed onto silica gel and chromatographed on a silica gel cartridge (Analogix®, Burlington, Wis., RS25-25) eluting with 20-100% ethyl acetate/hexanes to give (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl methanesulfonate: 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.27 (m, 4H), 7.27-7.20 (m, 1H), 4.96 (ddd, J=6.1, 7.6, 9.1, 1H), 3.71-3.44 (m, 1H), 2.94 (s, J=13.5, 3H), 2.85 (ddd, J=4.9, 8.1, 16.0, 1H), 2.75-2.68 (m, 2H), 2.67-2.55 (m, 1H), 2.54-2.44 (m, 1H), 2.31 (dd, J=4.1, 8.7, 1H), 2.20-2.04 (m, 1H), 1.97 (dtd, J=3.4, 6.2, 9.6, 1H), 1.79-1.63 (m, 1H), 1.61-1.49 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([Cl:21])[C:14]=1[OH:22].N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Cl:12][C:13]1[CH:18]=[C:17]([CH:16]=[C:15]([Cl:21])[C:14]=1[O:22][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:19][OH:20]
Reactant: OCc1cc(Cl)c(O)c(Cl)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a flask containing 24 ml of dichloromethane was added 4 A sieves (2.97 g, activated at 500° C. for 8 h), 4-methoxyphenylboronic acid (1.84 g, 12.0 mmol), 2,6-dichloro-4-hydroxymethylphenol (465 mg, 2.41 mmol), copper (II) acetate (438 mg, 2.41 mmol), pyridine (0.97 ml, 12.0 mmol) and triethylamine (1.67 ml, 12.0 mmol). The reaction flask was fitted with a drying tube and stirred overnight. Filtration through celite and removal of volatiles in vacuo followed by column chromatography (silica, 30% ethyl acetate in hexane) provided the title compound as light brown oil (323 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 6.82 (d, j=7.2 Hz, 2H), 6.77 (d, j=7.2 Hz, 2H), 4.69 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].Cl>ClCCl.O>[CH3:19][S:20]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:22])=[O:21]
Reactant: NCC(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
2-Aminoacetophenone hydrochloride (6.10 g, 35.5 mmol) was dissolved in dichloromethane (60 mL), and to the solution was added triethylamine (7.56 g, 74.9 mmol). The solution was cooled to 0° C., and to the solution was added methanesulfonyl chloride (2.84 mL, 36.5 mmol). The solution was stirred at the same temperature for 5 minutes, and then at room temperature for 2 hours. To the reaction mixture was added water and 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was suspended in chloroform (5 mL) and the suspension was stirred, and then, the resulted crystals were collected by filtration to obtain 2-(methylsulfonylamino)acetophenone (4.58 g, 57%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=C[CH:2]=1.[CH3:8][CH:9](C)[CH2:10][C:11](=[O:13])[CH3:12].[C:15]([O:18]CC)(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:5][CH2:6][CH:1]([CH3:2])[CH3:7])(=[O:17])[CH3:16].[CH3:12][C:11](=[O:13])[CH2:10][CH2:9][CH3:8]
Reactant: CCOC(C)=O
Reactant: CC(=O)CC(C)C
Reactant: Cc1ccccc1
Product: CC(=O)OCCC(C)C
Product: CCCC(C)=O
Reaction time: 0.33 h

Procedure:
On completion of the bioreduction stage the fermentation broth was centrifuged at 5000 rpm for 20 minutes at 20-22° C. The compound of formula (III) (R=t-butyl) was isolated from the supernatant by extraction with a suitable organic solvent such as toluene, isoamyl acetate, 2-pentanone, ethyl acetate or 4-methyl-2-pentanone, preferably ethyl acetate or 2-pentanone. The solvent extract was dried over anhydrous sodium sulphate and the solvent removed by vacuum distillation to afford the crude product of formula III (R=t-butyl) as a golden oil.
Reaction SMILES: NO.[Si:3](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:31][NH:32][OH:33]>ClCCl.O>[CH3:31][N:32]([Si:3]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:33]
Reactant: CNO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: NO
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(O)[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
One possible synthetic scheme for hydroxylamine derivatives involves adding tert-butyldiphenylsilyl chloride and N,N-diisopropylethylamine to a suspension of N-methyl hydroxylamine hydrochloride in dry dichloromethane. The reaction mixture was stirred followed by the addition of water. The two layers were separated and the aqueous layer was extracted with methylene chloride. The organic solutions were then combined, dried with magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting product was purified by liquid chromatography on silica gel using a mixture of hexane and ethyl acetate to elute the desired product. The purification process gave N-Methyl,N-(tert-butyldiphenylsilyl)hydroxylamine (27).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[O:12][C:13](=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:25].O>CC(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:9]=1[N:10]=[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[NH:25][C:13]2=[O:12])([O-:3])=[O:2]
Reactant: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12
Reactant: N
Solvent: CC(C)O
Solvent: O
Product: O=c1[nH]c(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Yield: 60.3 %

Procedure:
8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-4-one 3 (150 mg, 0.45 mmol) was added to a solution of ammonia (5.0 mL, 10 mmol) in IPA. The reaction mixture was heated under gentle reflux for 12 h then cooled to room temperature. The reaction mixture was poured into H2O and the resulting precipitate was collected by filtration rinsed with H2O and dried under vacuum. The crude residue was recrystallized from EtOAc to give 8 (91 mg, 62% yield) as a yellow solid.