Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].COC(O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]([F:18])([F:16])[F:17])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCC(F)(F)F)c1
Agent: COC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: Nc1cccc(S(=O)(=O)NCC(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A mixture of 3-nitro-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide (3.12 g, 11 mmol), sodium dithionite (8.09 g, 40 mmol), water (21.5 ml) and 2 methoxyethanol (21.5 ml) was stirred at 100° C. for 2 h, additional water (18.5 ml) was added at 70° C. and subsequently HCl (37%, 18.5 ml) was added over a period of 10 min (SO2 evolution). The reaction mixture was stirred at 70° C. for 20 min, poured into ice/water (50 ml) and sodium carbonate was added until the solution proofed to be basic. The solution was extracted with ethyl acetate (3×75 ml), the combined organic layers washed with brine (80 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) to yield the title compound (2.05 g, 73%) as a white solid. MS (ISP) 252.9 [(M−H)−]; m.p. 131° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([I:23])=[CH:20][CH:21]=3)[C:16](=[O:24])[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14]2)[CH2:9]1)=O)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[I:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH:14]=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:16]2=[O:24]
Reactant: CCOC(=O)c1cn([C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cn([C@@H]2CCNC2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 3 h

Procedure:
(S)-Ethyl 1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.2 g, 1.08 mmol) was dissolved in 1,4-dioxane (10 mL) and 4.0M hydrogen chloride in 1,4-dioxane (4 mL) was added. The reaction was stirred at 23° C. for 3 hours, and the solvent was removed in vacuo. The solid was then dried in a vacuum oven at 50° C. for 18 hours to give 1.03 g (quant. yield) of (R)-ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinoline-3-carboxylate hydrochloride as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:7][C:6]1=[O:22])[CH3:4].[CH2:23]([O:25][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Cl)[CH3:24]>CN(C=O)C>[CH2:23]([O:25][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:5]([CH2:3][CH3:4])[C:6]1=[O:22])[CH3:24]
Reactant: CCn1c(-c2ccccc2)c(-c2ccccc2)[nH]c1=O
Reactant: CCOC(=O)CCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(CC)c1=O

Procedure:
The product is obtained as described in example 1 from 2.1 g of NaH (80% suspension in mineral oil), 18.5 g of 1-ethyl-4.5-diphenyl-4-imidazolin-2-one, 140 cc. of DMF, 13.5 g of 7-chloroenanthic acid ethyl ester and 2.1 g of NaJ.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:41]=[C:40]2[N:35]([N:36]=[C:37](Cl)[CH:38]=[CH:39]2)[N:34]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:41]=[C:40]2[N:35]([N:36]=[C:37]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:38]=[CH:39]2)[N:34]=1)=[O:32])[CH3:26]
Reactant: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 25 °C
Reaction time: 28 h
Yield: 39.8 %

Procedure:
1.41 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.23 g of N-(6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 17 ml of N,N-dimethylformamide; 1.50 ml of N-ethyldiisopropylamine was added, followed by stirring at room temperature for 28 hours, then at 60° C. for 19 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated, recrystallized by the addition of tetrahydrofuran, collected by filtration, washed with ethyl ether and dried to yield 987 mg of the title compound.
Reaction SMILES: [N+]([O-])(O)=O.[CH:5]1([CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]2[C:16]([C:17]([O:19]C)=[O:18])=[CH:15][N:14]=[CH:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[Na+].O>C(O)(=O)C>[CH:21]1([CH:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:12]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[CH:13]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cncn1C(c1ccccc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C(O)c1cncn1C(c1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A mixture of 8.7 parts of methyl 1-(cyclohexylphenylmethyl)-1H-imidazole-5-carboxylate mononitrate, 9 parts of a sodium hydroxide solution 50% and 45 parts of water was stirred for 1 hour at reflux temperature. 35 Parts of water were added. After cooling, the reaction mixture was neutralized with acetic acid. The product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of ethanol and acetonitrile. The product was filtered off (the filtrate was set aside) and dried in vacuo at 50° C., yielding a first fraction of 2.1 parts (30.8%) of 1-(cyclohexylphenylmethyl)-1H-imidazole-5-carboxylic acid; mp. 249.5° C. (compound 1.251).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:17][CH:18]([CH3:40])[C@@H:19](OS(C)(=O)=O)[C:20]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:21].O>C1COCC1>[CH3:17][CH:18]([CH3:40])[C@@H:19]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:20]([NH:22][C@H:23]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1)[CH3:24])=[O:21]
Reactant: OCCOc1ccccc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OS(C)(=O)=O)C(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OCCOc2ccccc2)C(C)C)cc1
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
Under a nitrogen atmosphere, 2-phenoxyethanol (17.3 mL, 138 mmol) in THF (450 mL) is cooled to 5° C. using an ice water bath and treated dropwise over 5 min with a 1M solution of potassium tert-butoxide in THF (138 mL, 138 mmol). The mixture is stirred for 30 min, and methyl 4-[(1S)-1-[[(2R)-3-methyl-2-methylsulfonyloxy-butanoyl]amino]ethyl]benzoate (45 g, 126 mmol) is added in one portion. The mixture is stirred to room temperature for 1 h, and water (300 mL) is added. The layers are separated, and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with brine, dried over MgSO4, filtered, and concentrated. The crude material is purified using silica gel column chromatography (750 g cartridge; 20 to 60% ethyl acetate in heptane) to provide the title compound as a white solid (30 g, 60%). MS (m/z): 400.4 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][C:12](=O)[CH:13]([F:15])[F:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl.O>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:24]([C:23]4[CH:18]=[CH:19][C:20]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:22]=4)[N:25]=[C:12]([CH:13]([F:15])[F:14])[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CC(=O)C(F)F)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2ccc3c(c2)OCO3)cc1
Yield: 83.9 %

Procedure:
1-(1,3-Benzodioxol-5-yl)-4,4-difluorobutane-1,3-dione from Step 1 (2.4 g, 10 mmol) was dissolved in ethanol (100 mL). To the stirred mixture was added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours. The mixture was cooled and water was added until crystals slowly appeared. Filtration yielded a light tan solid (3.3 g, 84%): mp 214°-218° C.; 1H NMR (D6 -DMSO): 7.86 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 7.49 (brs, 2H), 7.3-6.7 (m, 5H), 6.06(s, 2H). Anal. Calc'd for C17H13N3SO4 F2 : C, 51.91; H, 3.33; N, 10.68. Found: C, 51.90; H, 3.25; N, 10.65.
Reaction SMILES: [OH:1][C:2]1[CH:52]=[CH:51][C:5]([CH2:6][CH:7]2[CH2:18][N:17]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15][N:14]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:13][CH2:12][N:11]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:10][CH2:9][N:8]2[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:55]([CH:57]1[O:59][CH2:58]1)Cl>C1(C)C=CC=CC=1>[O:59]1[CH2:58][CH:57]1[CH2:55][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:18][N:17]([CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15][N:14]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:13][CH2:12][N:11]([CH2:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:10][CH2:9][N:8]2[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:51][CH:52]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)C(Cc2ccc(O)cc2)CN(CC(=O)OC(C)(C)C)CC1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)C(Cc2ccc(OCC3CO3)cc2)CN(CC(=O)OC(C)(C)C)CC1

Procedure:
12.72 g (18.2 mmol) of 2-[4-hydroxybenzyl)-1,4,7,10-tetrakis-(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (example 9d) is dissolved in 250 ml of toluene and mixed with 350 mg of sodium hydride (80% in paraffin, 18.3 mmol). It is warmed to 80° to 100° C. and mixed by instillation with a solution of 1.74 g (18.2 mmol) of epichlorohydrin in 50 ml of toluene. After refluxing for two hours, it is concentrated by evaporation and purified over a silica gel column. A colorless oil is obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>CCOC(C)=O>[Cl:11][CH2:12][C:13]1[N:6]=[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[O:5][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccccc1F
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1nc(CCl)co1
Temperature: 130 °C
Yield: 65.8 %

Procedure:
A mixture of 2-fluorobenzamide (500 mg, 3.59 mmol) and 1,3-dichloroacetone (1.82 g, 14.36 mmol) was heated to 130° C. for 2 h in a sealed tube. The reaction mixture was diluted with EtOAc and washed with water and brine. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 2-3% EtOAc in petroleum ether) to afford 4-(chloromethyl)-2-(2-fluorophenyl)oxazole (500 mg, yield 66%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.08-8.02 (td, J=7.6 Hz, 1.6 Hz, 1H), 7.78 (s, 1H), 7.50-7.43 (m, 1H), 7.28-7.18 (m, 2H), 4.61 (d, J=0.7 Hz, 2H). MS (ESI) m/z: Calculated for C10H7ClFNO: 211.02. found: 211.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][CH3:20])=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(C(F)(F)F)c1
Yield: 95 %

Procedure:
A reactor is charged with 1 g (4.9 mmol) of 3-(trifluoromethyl)-4-methylbenzoic acid in 10 ml methanol in the presence of a catalytic amount of sulphuric acid. The mixture is heated for 6 hours at reflux. The solvent is then evaporated under reduced pressure and 100 ml of a saturated sodium bicarbonate solution is added to the mixture. The solution is extracted by 3*30 ml ethyl acetate. The organic phases are combined, dried on sodium sulphate and evaporated under reduced pressure to give the expected product (1 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(C)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:22][CH:21]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 73A. mp 151-152° C.; IR (KBr) cm−1: 3076, 3050, 1748, 1426, 1244, 1109; 400 MHz 1H NMR (DMSO-d6): δ 12.94 (br(s), 1H), 7.87 (s, 1H), 7.68-7.72 (m, 2H) 7.00-7.15 (m, 3H), 6.82-6.92 (m, 2H), 6.56 (d, 1H, J=8.5 Hz), 5.12 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.74 (t, 2H, J=7.5 Hz), 2.66 (t, 2H, J=7.5 Hz), 1.87 (pentet, 2H); MS m/z 521 (M−1). Anal. Calc'd for C26H22ClF3O4S: C, 59.71; H, 4.24. found: C, 59.54; H, 4.11.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:11])=[O:10])=[CH:5][C:4]=1[Cl:12].Cl>O1CCOCC1>[Cl:12][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[OH:2])[C:9]([NH2:11])=[O:10]
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(N)=O)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1ccc(O)c(Cl)c1

Procedure:
A mixture of 4-(aminocarbonyl)-2-chlorophenyl 1,1-dimethylethyl carbonate (6.86 g, 0.025 mol) and 4N HCl in dioxane (50 mL) in dioxane (30 mL) was heated at reflux for 4 hr. The reaction mixture was cooled, and precipitated solid was collected by filtration affording 3-chloro-4-hydroxybenzamide as a white solid, used without further purification. LC/MS (method E) tR 0.88 min; m/z 172 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6](OS(C)(=O)=O)[CH2:5][N:4]([CH3:13])[C:3]1=[O:14].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.C(Cl)Cl.C(O)(C)C>[N:15]([CH:6]1[CH2:7][N:2]([CH3:1])[C:3](=[O:14])[N:4]([CH3:13])[CH2:5]1)=[N+:16]=[N-:17]
Reactant: CN1CC(OS(C)(=O)=O)CN(C)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: ClCCl
Product: CN1CC(N=[N+]=[N-])CN(C)C1=O
Temperature: 70 °C
Reaction time: 13 h

Procedure:
To a solution of methanesulfonic acid 1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl ester (Step P6) (3.2 g, 14.3 mmol) in DMF (75 mL) at rt was added sodium azide (1.9 g, 28.7 mmol) and the mixture was stirred at 70° C. for 13 h. The mixture was diluted with CH2Cl2/isopropanol 3:1 and extracted with a saturated aqueous NaHCO3 solution. The organic phase was dried (Na2SO4), filtered and concentrated to afford the title compound. ESI-MS: [M+H]+ 170.1 (MS 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH:42]=O)[CH:33]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:42][C:34]6[CH:33]=[N:32][C:41]7[C:36]([CH:35]=6)=[CH:37][CH:38]=[CH:39][CH:40]=7)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Reactant: O=Cc1cnc2ccccc2c1
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCN(Cc4cnc6ccccc6c4)C5)n[nH]c3c2)cc1F

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and quinoline-3-carbaldehyde (72.9 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 27.8% yield, 34 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:28]#[C:27][CH2:26][OH:29])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: C#CCO
Reactant: O=C1Cc2cnc(Nc3ccc(I)cc3)nc2-c2ccc(Cl)cc2N1
Product: O=C1Cc2cnc(Nc3ccc(C#CCO)cc3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-36) and prop-2-yn-1-ol were converted to I-54 (86%): HRMS Calcd. for C21H15ClN4O2: 391.0961, Found 391.0960.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:17]=[CH:16][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[O:15])[NH:14][C:8]=2[CH:7]=1)([O-:5])=[O:4].I[CH3:19]>CN(C=O)C>[CH3:19][N:14]1[C:8]2[CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:17]=[CH:16][C:9]=2[CH2:10][CH2:11][CH2:12][C:13]1=[O:15]
Reactant: CI
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Reaction time: 0.25 h

Procedure:
144 mg of NaH (50%) are added to a solution of 549 mg of 8-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 15 ml of DMF. The reaction medium is stirred for 15 minutes and then 187 μl of iodomethane are added. The mixture is stirred for 16 hours at ambient temperature and then run into ice-cold water and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up in diisopropyl ether and the insoluble material is filtered off and dried under vacuum, so as to give 405 mg of 1-methyl-8-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:30][CH2:31]Br>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:31][CH2:30]2)=[O:16])=[C:4]([CH3:17])[CH:3]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CC1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
Into a 250 milliliter three-necked round-bottom reaction flask equipped with a mechanical stirrer, thermometer and nitrogen inlet and outlet was added 5.0 grams (17.0 mmol) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate prepared as in Example A, 5.73 grams (42.0 mmol) of anhydrous potassium carbonate, 20 milliliters of anhydrous dimethylformamide and 1.7 milliliters (20.0 mol) of 1,2-dibromoethane. The resulting mixture was stirred at ambient temperature under a nitrogen atmosphere and irradiated with ultra sound waves using a Bransonic 52 ultrasonic cleaning bath for a period of 4.25 hours. Ice was added to maintain the temperature of the bath between 26° C. and 31° C. After this period, high pressure liquid chromatographic analysis showed the reaction to be complete. The product was isolated by diluting with methylene chloride, filtering off the solids and concentrating under reduced pressure to give a yellow solid. Chromatography on silica gel with a 3:1 volume/volume hexane-ethyl acetate eluent provided 4.58 grams (14.0 mmol) of ethyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopropanecarboxylate as a pale yellow solid having a melting point of 87° C.-89° C. The total yield was 87 percent based on a 96.7 weight percent assay of the starting ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate. NMR analysis of the product indicated the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:19][C:18]1[C:13]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
p-Methoxyphenol (1.5 g) was added to a suspension of sodium hydride (0.6 g 50% oil dispersion, washed with petroleum) in dry dimethyl sulphoxide (30 ml) and the mixture stirred for 15 minutes. A solution of the combined products (1.5 g) from several preparations carried out as described in paragraph (d), in dimethylsulphoxide (20 ml) was added to the reaction mixture and heated to 60° C. for four hours. A further amount of sodium hydride (0.3 g of 50% oil dispersion, washed with petroleum), and potassium carbonate (1.38 g) was added. Heating was continued for another 4 hours. The mixture was poured into ice and water, and extracted with ether (400 ml). The ether extracts were washed with water, dilute sodium hydroxide, and water, dried, and evaporated to give the product.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=12.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][C:3]1[N:4]2[C:5]([S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=32)=[N:1][N:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)sc1nncn12
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1nnc2sc3ccccc3n12
Temperature: 25 °C

Procedure:
s-Triazolo(3,4-b)benzothiazole (6.4 grams; 0.0366 mole) was slurried with 200 milliliters of carbon tetrachloride, with stirring, at room temperature, and then heated. N-Bromosuccinimide (6.8 grams; 0.0366 mole plus 5 percent) was added and the solution refluxed and a pinch of azobisisobutylnitrile added to initiate the reaction. Subsequently the reaction mixture was filtered to separate blackish crystals, which were washed with carbon tetrachloride. The carbon tetrachloride was removed by evaporation, to yield a purple solid. This was chromatographed on a column packed with silica gel and eluted with ethyl acetate. The second portion was analyzed by elemental analysis and NMR, which confirmed its identity as the expected 3-bromo-s-triazolo(3,4-b)benzothiazole, m.p., 166°-7° C.