Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:38])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][NH:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:28][S:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:31])=[O:30])[C:6]([OH:38])=[O:5])=[O:27])=[CH:16][CH:15]=2)[N:25]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCc2cccc(N)n2)cc1)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(CCOc2ccc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2)n1

Procedure:
Ester 30-6 (120 mg, 0.22 mmol) was dissolved in 1 mL CH2Cl2, and 1 mL TFA was added. After 1 h the reaction was concentrated azeotroped with toluene, chromatographed (silica, 18:1:1→9:1:1→CH2Cl2 /MeOH/HOAc) and purified by prep HPLC (C18, 0.1% TFA in H2O/CH3CN) providing 30-7 as a white solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:12]=2[NH2:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+].[Cl-].[NH4+]>C(OC)(OC)OC.CCOC(C)=O>[C:1]1([S:7]([C:10]2[C:11]3[C:12](=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[CH:14]=[CH:15][CH:16]=3)[NH:24][CH:25]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCN(c2cccc(CS(=O)(=O)c3ccccc3)c2N)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Product: CN1CCN(c2cccc3c(S(=O)(=O)c4ccccc4)c[nH]c23)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 767.1 %

Procedure:
To a solution of 2.3 g of 2-benzenesulfonylmethyl-6-(4-methyl-piperazin-1-yl)-phenylamine in 20 mL trimethyl orthoformate was added p-toluenesulfonic acid (120 mg). The mixture was heated under reflux in a nitrogen atmosphere for 2 hours. The mixture was cooled to 60° C. and one flake of KOH was added. The mixture was reheated to reflux for 1.5 hours. The heating oil bath was turned off and the mixture stirred overnight under nitrogen. The mixture was treated with 50 mL saturated ammonium chloride solution and 100 mL EtOAc. The purple organic layer was separated from the clear aqueous solution, and washed with water (45 mL) and evaporated to a foam. This foam was dissolved in 80 mL 200 proof EtOH. After dissolution, the freebase crystallized. This mixture was heated under reflux to redissolve the solid, and after removal of the heating, 5 mL of a saturated solution of HCl in ethanol was added to this mixture. The mixture was cooled with stirring to room temperature and seeded to ensue immediate crystallization. The mixture was concentrated to ca. 40 mL and filtered. This collected solid was washed with ca. 3 mL EtOH and vacuum oven dried at 50° C. to give 1.9 g 3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H-indole (501) mp 160-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:11]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: CCN(CC)CCBr
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)cc(F)c21
Temperature: 95 °C

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 15 (0.96 g) is dissolved in DMF (7 mL), and K2CO3 (1.38 g) and 2-bromo-N,N-diethylethylamine hydrobromide (1.30 g) are added. The reaction mixture is heated to 95° C. for 16. Water is added and an oily solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-3% MeOH/CHCl3) gave 0.373 g of the title compound which is crystallized from ethyl acetate to give 0.163 g of a solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:24]1([N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCN(C(=O)c1ccccc1)C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N(CCCCCCO)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
N-(6-((tert-butyldimethylsilyl)oxy) hexyl)-N-cyclohexylbenzamide (242 mg, 0.58 mmol) was dissolved in THF (2 mL) and treated with TBAF (1M in THF, 0.72 mL, 0.72 mmol). The mixture was stirred at room temperature for overnight. The mixture was then concentrated and purified on silica gel with ethyl acetate:hexanes from 2:8 to 1:1 gave the desired product as a clear oil (136 mg, 77%). 1H NMR (300 MHz, CDCl3): δ 7.42-7.29 (m, 5H), 3.75-2.98 (m, 5H), 1.98-0.80 (m, 19H).
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:9]([OH:11])=O)[CH2:5][C:6]([OH:8])=[O:7])=[O:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].Cl.[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29]>C(O)(=O)C>[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:9](=[O:11])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=CN[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Reaction time: 5 h

Procedure:
In 28.6 g of acetic acid, 16.1 g (0.1 mole) of N-formyl L-aspartic acid was suspended and 10.2 g (0.1 mole) of acetic anhydride was added. The mixture was warmed to 50°-55° C. and stirred for 5 hours at the same temperature. After finishing the reaction, the resulting mixture was cooled to 15°-20° C. and then 9.2 g (0.11 mole) of sodium acetate and 20.5 g (0.095 mole) of L-phenylalanine methyl ester hydrochloride were successively added at the same temperature. The reaction was carried out for 4 hours with stirring at the same temperature. The reaction mixture was then concentrated and 57.2 g of water was added and cooled to 10°-15° C. Precipitated crystals were filtered, washed and dried. Crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester thus obtained were 28.2 g. The crystals were analyzed by high performance liquid chromatography to give a ratio of α-isomer:β-isomer of 81.0:19.0. The crystals were purified with a conventional method to give high purity crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester. The yield was 20.8 g (68.0% yield on L-phenylalanine methyl ester hydrochloride).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=O)[C:7](=[CH:19]N(C)C)[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.Cl.[C:27]([NH2:30])(=[NH:29])[CH3:28].C[O-].[Na+]>CO.C(Cl)Cl.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:30]=[C:27]([CH3:28])[N:29]=[CH:19][C:7]=3[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1C[N+]([O-])=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1 g (2.8 mmole) of 8-chloro-1-(2-chlorophenyl)-4-[(dimethylamino)methylene]-3,4-dihydro-5H-2-benzazepine-5-one-2-oxide, 1.0 g (11 mmole) of acetamidine hydrochloride and 2.0 ml (9.9 mmole) of a 4.46M methanol sulution of sodium methoxide in a mixture of 20 ml of methanol and 20 ml of methylene chloride was stirred at room temperature for 2 hr. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Recrystallization of the residue from a mixture of ether and methylene chloride gave a colorless solid, mp 215°-216° C.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:18](O)[CH2:19][OH:20].CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:18]1[CH2:19][O:20][C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:1]1
Reactant: CCCCCCCCCC(=O)CC(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCCC1(CC(=O)OCC)OCCO1
Yield: 79 %

Procedure:
The mixture of ethyl 3-oxododecanoate (1.456 g, ca. 5 mmol), ethylene glycol (2.78 mL, 50 mmol) and a catalytic amount of p-TsOH (95 mg, 0.5 mmol) in benzene (50 mL) was heated to 110° C. under an argon atmosphere overnight. The solvent was removed, and the residue was diluted with 50 mL ethyl acetate. The solution was washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), and the organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (hexane/EtOAc 8:1, Rf=0.21) to give ethyl 3,3-ethylenedioxydodecanoate (1.131 g, 3.95 mmol) in 79% overall yield for the above two steps. 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J=7 Hz, 3H), 1.20-1.44 (m, 17H), 1.76-1.82 (m, 2H), 2.65 (s, 2H), 3.94-4.04 (m, 4H), 4.16 (q, J=7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.6, 23.4, 29.22, 29.43, 29.48, 29.62, 31.8, 37.7, 42.5, 60.4, 65.0, 109.4, 169.5.
Reaction SMILES: [Na].Cl.[CH3:3][C:4]([CH3:17])([CH:11](Cl)[CH:12]=[C:13]([Cl:15])[Cl:14])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)C>[CH3:3][C:4]1([CH3:17])[CH:11]([CH:12]=[C:13]([Cl:15])[Cl:14])[CH:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Thereafter, 2.8 parts of metallic sodium were dissolved in 150 parts of anhydrous ethanol, and 27.4 parts of ethyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate prepared by the process described above, were added to the solution. The mixture was agitated for 2 hours under reflux of ethanol. The reaction mixture was cooled by ice water and neutralized with hydrogen chloride-saturated ethanol solution. The precipitated solids were removed by filtration, and ethanol was distilled from the filtrate. The filtrate was diluted with diethyl ether, washed with water and then dried on anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was subjected to distillation under reduced pressure to obtain 21.0 parts of ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)cyclopropane carboxylate having a boiling point of 72° to 73° C. under 0.3 mmHg. The yield was 89%. The cis:trans ratio of the product determined by gas chromatography was 25:75.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:10]([CH2:24][CH2:25]O[Si](C(C)(C)C)(C)C)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:39][C:40]([S:43]([N:45]=[C:46]1[CH2:49][O:48][CH2:47]1)=[O:44])([CH3:42])[CH3:41]>CCCCCC.C1COCC1>[CH:24]([N:10]1[C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)=[CH:12][C:8]([C:4]2[CH:3]=[C:2]([C:46]3([NH:45][S:43]([C:40]([CH3:39])([CH3:41])[CH3:42])=[O:44])[CH2:49][O:48][CH2:47]3)[CH:7]=[CH:6][CH:5]=2)=[N:9]1)=[CH2:25]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: CC(C)(C)[Si](C)(C)OCCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-{3-(3-Bromophenyl)-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-1-yl}-1-(tert-butyldimethylsilyloxy)ethane (4.2 g, 7.8 mmol) was dissolved in 40 mL of hexane (dried over Na2SO4) and 15 mL THF (freshly distilled from CaH2). The solution was sparged with argon and cooled to −78° C. To the stirred solution was added nBuLi (6.21 mL of a 2.5 M solution in hexanes, 15.5 mmol) and the mixture was stirred for 15 min. LCMS showed incomplete reaction, so more nBuLi (1.0 mL, 2.5 mmol) was added and the mixture was stirred for 10 min. 2-Methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1.4 g, 7.8 mmol) was dissolved in 10 mL of THF (freshly distilled from CaH2) and cooled to −78° C. The cold solution of sulfinamide was added via cannula into the cold solution of anion. The resulting mixture was stirred for 10 min, then quenched by addition of 20% aqueous NH4Cl solution. The mixture was warmed to ambient temperature and extracted with EtOAc. The EtOAc layer was washed with water and brine, then dried over MgSO4, and the solvents were removed under reduced pressure. The residue was chromatographed on a 120 g silica gel column using 0-100% EtOAc:hexanes over 36 min at 85 mL/min. The product-containing fractions were combined and the solvents were removed under reduced pressure to give N-{3-[3-(1-ethenyl-5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl)phenyl]oxetan-3-yl}tert-butylsulfinamide as an oil. Calcd (M+1)+: 506.6. Found: 506.3
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]1([NH:21][C:22]2[CH:31]=[C:30]3[C:25]([C:26](=[O:39])[C:27]([CH:37]=O)=[CH:28][N:29]3[CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:24][C:23]=2[F:40])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1.C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCCl>[CH:15]1([NH:21][C:22]2[CH:31]=[C:30]3[C:25]([C:26](=[O:39])[C:27]([CH2:37][NH:41][C:42]4[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=4)=[CH:28][N:29]3[CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[CH:24][C:23]=2[F:40])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Nc1ccc(O)cc1
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=c1c(CNc2ccc(O)cc2)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reaction time: 24 h

Procedure:
169 mg of sodium triacetoxyborohydride was added to a mixed solution 10 ml of 1,2-dichloroethane and 0.05 ml of acetic acid of 142 mg 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde and 66 mg of 4-aminophenol, followed by stirring for 24 hours. Aqueous saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and subsequent filtration, concentration under a reduced pressure was carried out. The resulting residue was purified by silica gel column chromatography and then crystallized from ethyl acetate to obtain 46 mg of [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-{[(4-hydroxyphenyl)amino]methyl}quinolin-4(1H)-one.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:42]=[CH:41][C:18]3[C:19]4[N:23]([CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[C:22]2[CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=[CH:30][C:21]=2[C:20]=4[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:9]1)=O)(C)(C)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[CH:35]1([C:20]2[C:21]3[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][C:22]=3[N:23]3[C:19]=2[C:18]2[CH:41]=[CH:42][C:15]([O:14][CH:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)=[CH:16][C:17]=2[O:26][CH2:25][CH2:24]3)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCN(C(=O)OC(C)(C)C)C2)ccc1-3
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCNC2)ccc1-3
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
Methyl 3-(1-tert-butoxycarbonylpiperidin-3-yloxy)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (0.68 g) was dissolved in trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 3 hr. Toluene was added to the reaction mixture and the solvent was evaporated under reduced pressure. 4N HCl-ethyl acetate solution (2.0 ml) was added to the obtained residue and the mixture was stirred, and the solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=9:1) to give methyl 12-cyclohexyl-3-(piperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (0.16 g, yield 17%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.CCOC(C)=O>[CH:15]1([CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: O=C1CCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2c(OCC3CC3)cccc21
Temperature: 80 °C
Yield: 79.9 %

Procedure:
To a solution of 5-hydroxy-1-tetralone (1.8 g, 11.0 mmol) in butanone was added (bromomethyl)cyclopropane (1.8 g, 13.2 mmol) and K2CO3 (3.0 g, 22.0 mmol) at rt. The mixture was heated at 80° C. overnight. After the reaction was cooled to rt, it was diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (20:1 PE/EtOAc) to give 1.9 g (78%) of the title compound as a tan oil. 1H NMR (300 MHz, CDCl3): δ 0.35-0.40 (2H, m), 0.62-0.68 (2H, m), 1.27-1.32 (1H, m), 2.05-2.17 (2H, m), 2.64 (2H, t, J=6.6 Hz), 2.96 (2H, t, J=6.0 Hz), 3.86 (2H, d, J=6.9 Hz), 6.98 (1H, d, J=8.1 Hz), 7.24 (1H, t, J=8.7 Hz), 7.65 (1H, d, J=8.1 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(C(C)(C)C)cc4)cc3=O)ccc2nn1C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a solution of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (100 mg) in N,N-dimethylformamide (2 ml) were added 1-(bromomethyl)-4-(tert-butyl)benzene (98 mg) and potassium carbonate (108 mg) at room temperature, and the mixture was stirred at the same temperature for 18 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) and recrystallized from ethyl acetate to give the title compound (40 mg).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@@H:18]1[C:23]([C:24]([CH3:26])=[CH2:25])=[CH:22][C@@H:21]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[NH:20][CH2:19]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(ON[C@H]1CN[C@@H](C(N)=O)C=C1C)C=C>>[CH2:1]([O:4][NH:5][C@@H:18]1[C:23]([C:24]([CH3:26])=[CH2:25])=[CH:22][C@@H:21]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[NH:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(=C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON[C@H]1CN[C@@H](C(N)=O)C=C1C
Product: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(=C)C

Procedure:
The desired product was prepared from N-(allyloxy)-N-((3R,6S)-6-((tert-butyldimethylsilyloxy)methyl)-4-(prop-1-en-2-yl)-1,2,3,6-tetrahydropyridin-3-yl)-2-nitrobenzenesulfonamide (Intermediate 55, 2.45 g, 4.68 mmol) following the procedure described for Intermediate 22. The desired product was obtained as yellow oil (1.19 g, 75%).
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[C:37]1[C:41]([C:42](Cl)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[C:37]1[C:41]([C:42]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)O[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 633.6 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][C:11]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[CH3:10][C:11]1[C:19]([CH3:20])=[CH:18][C:17]([N+:1]([O-:4])=[O:2])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of nitric acid (d=1.42:20 ml) and sulfuric acid (d=1.84:20 ml) was added 2,3-dimethyl benzoic acid (6.0 g) at 0° C. After stirring for 3 hours, the mixture was poured into ice water (300 ml). The organic layer was extracted with ethyl acetate (100 ml) and washed with water (100 ml×3). The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by a column of silica gel to give a yellow solid of 2,3-dimethyl-5-nitrobenzoic acid (1.80 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:20]=[C:21]([CH2:23]O)[N:22]=[C:16]4[C:15]=3[CH2:25][CH2:26][CH3:27])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.COCCN(S(F)(F)[F:38])CCOC.C([O-])(O)=O.[Na+].C(=O)=O>ClCCl>[F:38][CH2:23][C:21]1[N:22]=[C:16]2[N:17]([CH:18]=[N:19][C:14]([CH2:13][N:9]3[CH:10]=[CH:11][N:12]=[C:8]3[C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:15]2[CH2:25][CH2:26][CH3:27])[N:20]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(CO)nc12
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(CF)nc12
Reaction time: 2 h

Procedure:
To a solution {7-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}-methanol (compound 223, below) (31 mg, 0.08 mmol) in dichloromethane (5 mL) is added bis(2-methoxyethyl)aminosulfur trifluoride (0.2 ml, 50% in THF) at room temperature under N2. The mixture is stirred for two hours, and is poured into saturated NaHCO3 (10 mL), and after CO2 evolution ceases it is extracted into dichloromethane, dried (MgSO4), filtered and evaporated in vacuo. PTLC by 5% MeOH/dichloromethane gives the pure product (157). 1H NMR: 0.98 (3H, t, J=5.4 Hz), 1.67 (2H, m), 2.99 (2H, m), 5.69 (2H, d, J=35.1 Hz), 5.88 (2H, s), 7.22 (1H, s), 7.22–7.31 (2H, m), 7.54 (1H, t, J=6.0 Hz), 8.39 (1H, s), 9.13 (1H, s). LCMS (M+1) 370.20.