Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([N+:30]([O-])=O)[CH:29]=1)[C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]([F:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[CH3:26])=[O:7])#[N:2].[Sn](Cl)(Cl)(Cl)Cl.Cl>C(O)(C)C>[NH2:30][C:28]1[CH:29]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]([CH:27]=1)[C:6]([NH:8][C:9]1[C:10]([CH3:26])=[CH:11][C:12]([C:16]([F:25])([C:17]([F:18])([F:19])[F:20])[C:21]([F:22])([F:23])[F:24])=[CH:13][C:14]=1[CH3:15])=[O:7]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(C#N)cc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(C)O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)cc(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
3-Cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-5-nitro-benzamide (12.0 g, 25.9 mmol) (Example I8) was dissolved in isopropanol (200 ml) and tin chloride (14.73 g, 77.7 mmol) was added. The mixture was cooled to 0° C. and aqueous hydrochloric acid (concentrated) (30 ml) was added slowly. The reaction mixture was stirred at 80° C. for 0.5 hours. ⅓ of the total volume of isopropanol was evaporated. Water (100 ml) was added to the concentrated mixture and aqueous sodium hydroxide (4N) was added to adjust the pH to 7-8. The aqueous phase was extracted three times with ethyl acetate (3×200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1 to 0:1) to give 5-amino-3-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (10.6 g, 94.4% yield). 1H-NMR (400 MHz, CDCl3): 7.47 (s, 1H), 7.44 (s, 2H), 7.36 (s, 2H), 7.07 (s, 1H), 4.11 (bs, 2H), 2.32 (s, 6H) ppm.
Reaction SMILES: [CH:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1)([CH3:3])[CH3:2].Cl[C:15]1[N:23]=[C:22]2[C:18]([N:19]=[C:20]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([C:32]([OH:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]3)[N:21]2[CH3:24])=[C:17]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:16]=1>>[OH:35][C:32]([CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:20]2[N:21]([CH3:24])[C:22]3[C:18]([N:19]=2)=[C:17]([N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)[N:16]=[C:15]([N:5]2[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:12](=[O:13])[N:4]2[CH:1]([CH3:3])[CH3:2])[N:23]=3)[CH2:31][CH2:30]1)([CH3:34])[CH3:33]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)n1[nH]c2ccccc2c1=O
Product: CC(C)n1c(=O)c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-isopropyl-1,2-dihydroindazol-3-one and 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol were reacted to give 443. LCMS m/z: 549.3 (MH+)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>C(O)=O>[CH2:1]([O:8][C:9](=[O:26])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(CC(=O)OCc2ccccc2)cc1
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=C(O)CCc1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 87 %

Procedure:
1,1-dimethylethyl 3-[4-(2-benzyloxy-2-oxoethyl)phenyl]propanoate (3.0 g, 8.5 mmol) was stirred in formic acid (10 mL) for 8 hours. Removal of the solvent in vacuo provided a colorless oil that was shaken vigorously with a mixture of ethyl acetate and hexanes (1:3, 20 mL) until it solidified. The mixture was cooled in ice water and the product, collected by suction filtration to give 3-[4-(2-benzyloxy-2-oxoethyl)phenyl]propanoic acid, as a white solid (2.2 g, 7.4 mmol) in 87% yield, mp. 62°-64.5° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.CN(C)[CH:17]=[O:18].Cl>CCCCCC.C(OCC)C>[Br:14][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([Br:13])[CH:10]=1)[CH:17]=[O:18]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cc(Br)cc(Br)c1
Temperature: -80 °C
Reaction time: 1 h

Procedure:
0.222 mol of a solution of n-butyllithium in hexane is added dropwise at −80° C. to 0.222 mol of 1,3,5-tribromobenzene in 1.8 liters of ethyl ether. The reaction mixture is stirred at −80° C. for one hour. A solution of 0.222 mol of N,N-dimethylformamide in 50 ml of ethyl ether is slowly added. The temperature is maintained at −80° C. for one hour, before being brought to ambient temperature. Stirring is carried out for one night. 450 ml of 1N hydrochloric acid are added. The reaction mixture is extracted with ether. The organic phases are collected and dried over magnesium sulphate. After filtration and removal of the solvents by evaporation, the crude product is purified by chromatography on a silica column (eluant: cyclohexane/ethyl acetate: 95/5).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:9])=[C:6]([Cl:23])[CH:5]=1)([O-:3])=[O:2].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C1CCN2C(=NCCC2)CC1>C(#N)C>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[C:6]([Cl:23])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1C=CC=Nc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CN1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ccccc21

Procedure:
1-[4-Nitro-2-chlorobenzoyl]-1,5-benzodiazepine (5 g) and ethyl bromoacetate (16.7 ml) are dissolved in acetonitrile (100 ml), and thereto is added dropwise 1,8-diazabicyclo[5.4.0]-7-undecene (11.3 ml). The mixture is refluxed for two days, concentrated, and thereto are added water and chloroform, and extracted. The extract is dried over sodium carbonate, and purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=4:1→1:1) to give 1-(4-nitro-2-chlorobenzoyl)-5-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (4.4 g) as pale yellow oil.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[OH:21]>CN(C)C=O.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[O:21][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Oc1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2c(F)cccc2F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
Into a 500-mL 4-necked round-bottom flask, was placed a solution of sodium hydride (4.05 g, 168.75 mmol, 1.70 equiv) in N,N-dimethylformamide (200 mL). A solution of 1-fluoro-4-nitrobenzene (14 g, 99.22 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 0° C. over 20 min. The resulting solution was stirred for 2 hr at room temperature. Cu2Cl2 (9.83 g, 100.31 mmol, 1.01 equiv) was added and a solution of 2,6-difluorophenol (15.5 g, 119.15 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 25° C. over 10 min. The resulting solution was stirred for 12 h at 100° C. in an oil bath, diluted with 500 mL of water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was placed on a silica gel column and eluted with ethyl acetate/petroleum ether (1/8) to give 20 g (80%) of 1,3-difluoro-2-(4-nitrophenoxy)benzene as brown oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([N:15]3[CH2:20][CH2:19][CH2:18][N:17]4[C:21]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)=[N:22][N:23]=[C:16]34)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[N:27]1[CH:26]=[CH:25][C:24]([C:21]2[N:17]3[CH2:18][CH2:19][CH2:20][N:15]([CH:13]([C:10]4[N:11]=[N:12][N:8]([C:4]5[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=5)[C:30]#[N:31])[N:9]=4)[CH3:14])[C:16]3=[N:23][N:22]=2)=[CH:29][CH:28]=1
Reactant: CC(c1nnn(-c2cccc(I)c2)n1)N1CCCn2c(-c3ccncc3)nnc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(c1nnn(-c2cccc(C#N)c2)n1)N1CCCn2c(-c3ccncc3)nnc21

Procedure:
The title compound is prepared from 8-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=O)=[CH:4][CH:3]=1.[I-].[CH3:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:14])=[CH:4][CH:3]=1
Reactant: O=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the aldehyde from Example 28C [(1S,2S)-2-(4-bromophenyl)cyclopropanecarbaldehyde] and methyltriphenylphosphonium iodide [CAS 2065-66-9] in anhydrous dichloromethane was stirred at 0° C. under N2. Potassium t-butoxide was added to this chilled mixture. The ice bath was removed and the mixture was stirred at room temperature for one hour. The mixture was quenched with saturated aqueous NH4Cl. The mixture was extracted with dichloromethane and the combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel with hexanes to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:18])[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[N:8]2[CH2:13][CH2:12][CH2:11][S:10][C:9]=12)([O-])=O.[C:19](O)(=[O:21])[CH3:20]>[Zn]>[C:19]([NH:1][C:4]1[C:5](=[O:18])[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[N:8]2[CH2:13][CH2:12][CH2:11][S:10][C:9]=12)(=[O:21])[CH3:20]
Reactant: CCCn1c(=O)c([N+](=O)[O-])c2n(c1=O)CCCS2
Reactant: CC(=O)O
Agent: [Zn]
Product: CCCn1c(=O)c(NC(C)=O)c2n(c1=O)CCCS2
Yield: 79 %

Procedure:
Zinc powder (1,21 g) was added to a solution of 9-nitro-7-propyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (1 g) in acetic acid (10 ml) and the mixture was refluxed for 4 hours. An insoluble material was removed by filtration, and the filtrate was concentrated to obtain syrup. The syrup was purified by column chromatography on silica gel. The resulting crude crystals were recrystallized from methylene chloride-hexane to give colorless needles (0.83 g, 79%).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][C:9]3[CH2:15][CH2:14][CH2:13][C:10]=3[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Cu].C1(C)C(C)=CC=CC=1>[C:19]1([CH2:18][O:1][C:2]2[C:7]3=[N:8][C:9]4[CH2:15][CH2:14][CH2:13][C:10]=4[C:11](=[O:12])[N:6]3[CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1c2c(nc3c(O)cccn13)CCC2
Reactant: BrCc1ccccc1
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: O=c1c2c(nc3c(OCc4ccccc4)cccn13)CCC2

Procedure:
A stirred mixture of 6.1 g. of 2,3-dihydro-5-hydroxycyclopenta[d]pyrido[1,2-a]pyrimidin-10(1H)-one, 1.40 g. of powdered sodium hydroxide, 100 ml of xylene, 100 mg of copper bronze, and 6.2 g. of benzyl bromide are stirred and heated under reflux for 12 hours, and filtered hot. From the filtrate, on cooling, the product crystallizes. It is filtered and recrystallized from xylene to give 6.3 g. of product, m.p. 150°-152°.
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)[CH2:6][O:7][C:8](=[O:13])/[CH:9]=C(\N)/C.COC1C=C(C=C(OC)C=1OC)COC(C1[CH:31]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N+:48]([O-:50])=[O:49])[C:32]([C:38]([O:40]C)=O)=C(C)NC=1C)=O>C(O)C>[CH3:6][O:7][C:8]([CH2:9][C:38](/[CH:32]=[CH:31]/[C:42]1[C:43]([N+:48]([O-:50])=[O:49])=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:40])=[O:13]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2cc(OC)c(OC)c(OC)c2)C1c1ccccc1[N+](=O)[O-]
Reactant: COc1cc(COC(=O)/C=C(/C)N)cc(OC)c1OC
Solvent: CCO
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]
Yield: 78 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 ml of β-aminocrotonic acid 3,4,5-trimethoxybenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3,4,5-trimethoxybenzyl ester of melting point 125° C (from ethanol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][C:25]1([CH3:31])[NH:29][C:28](=[O:30])[CH2:27][CH2:26]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:29]4[C:25]([CH3:31])([CH3:24])[CH2:26][CH2:27][C:28]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC1(C)CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4(C)C)cc3)CC2)c(C)c1
Yield: 18 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (295 mg) described in Preparation Example 113 and 5,5-dimethylpyrrolidin-2-one (79 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (51 mg) was obtained.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH2:6]([NH:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[C:13]([CH3:31])=[C:12]([F:32])[CH:11]=1)[CH3:7]>CN(C=O)C>[CH2:1]([NH:3][C:4]([N:28]1[CH2:29][CH2:30][CH:25]([C:20]2[C:19]3[C:23](=[CH:24][C:16]([C:14]4[CH:15]=[C:10]([C:9]([NH:8][CH2:6][CH3:7])=[O:33])[CH:11]=[C:12]([F:32])[C:13]=4[CH3:31])=[CH:17][CH:18]=3)[NH:22][N:21]=2)[CH2:26][CH2:27]1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4CCNCC4)n[nH]c3c2)c1
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4CCN(C(=O)NCC)CC4)n[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl isocyanate (6.5 μL) and N-ethyl-3-fluoro-4-methyl-5-[3-(4-piperidinyl)-1H-indazol-6-yl]benzamide (Intermediate 22, 30 mg) in DMF (3 mL) was stirred at room temperature under nitrogen for 30 min. The solvent was removed under vacuum and the residue was purified by preparative HPLC to give the title compound as a white solid (18 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH2:17][N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19]2)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
N-Benzylmaleimide (5.0 g, 26.7 mmol), and N-(methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (7.0 g, 29.4 mmol) were dissolved in toluene (150 mL). Trifluoroacetic acid (500 μL, 6.5 mmol) was added at room temperature. The reaction was allowed to stir for two hours at room temperature, and the precipitate was filtered off (˜440 mg). The filtrate was concentrated and purified by silica gel column chromatography (20-50% ethyl acetate in hexanes) to afford a white solid (6.2 g, 72%). 1H NMR (400 MHz, CDCl3): δ 7.22-7.05 (m, 8H), 7.01-6.96 (m, 2H), 4.45 (s, 2H), 3.95 (s, 2H), 3.50 (d, J=11.0 Hz), 3.37 (d, J=8.8 Hz), 3.10 (app t, J=9.1 Hz); 13C NMR (400 MHz, CDCl3): δ 175.8 (C═O), 134.8 (Ph), 130.6 (Ph), 129.6 (Ph), 129.3 (Ph), 128.8 (Ph), 128.6 (Ph), 128.3 (Ph), 127.7 (Ph), 57.3 (CH2), 54.0 (CH2), 42.9 (CH), 42.6 (CH2).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:6])[CH2:4][CH3:5].[H-].[Na+].CO[C:11](=O)[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>CN(C)C=O>[CH2:4]([C:3]1[N:6]=[C:11]([CH2:12][CH2:13][NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[O:1][N:2]=1)[CH3:5]
Reactant: COC(=O)CCNC(=O)OC(C)(C)C
Reactant: CCC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
2.00 g (22.70 mmol) N-hydroxy-propionamidine are placed in 10 ml dimethylformamide and molecular sieve. 0.999 g (24.97 mmol) sodium hydride (60% in mineral oil) are added. The mixture is stirred for 0.1 hours at 50° C., then 5.00 g (24.60 mmol) methyl3-tert-butoxycarbonylamino-propionate in 20 ml dimethylformamide are added. The reaction mixture is stirred for 3 hours at 50° C. After cooling 15 ml of water are added, and the mixture is suction filtered through Celite. The 2 phases of the filtrate are separated and the organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH:9]([OH:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1)[CH3:2].[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>N1C=CC=CC=1>[C:15]([O:12][CH:9]([CH2:10][CH3:11])[CH2:8][O:7][C:6]1[CH:13]=[CH:14][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CCc1ccc(OCC(O)CC)cc1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCc1ccc(OCC(CC)OC(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Cooling in an ice bath 0.93 g (5 mmol) of 1-(p-ethylphenoxy)-butan- 2-ol was dissolved in 10 ml of pyridine, and to this solution was added dropwise 0.53 g (5 mmol) of isobutyryl chloride. The mixture was stirred at room temperature for 3 hours after the addition was completed. The reaction mixture was treated in the same manner as in Example 7, and purified by column chromatography using silica gel to afford 1.3 g of 1 -(p-ethylphenoxy)-butan-2-ol isobutyrate (compound No. 15) in a yield of 83% as a colorless oily substance. The refractive index of the product was nD32 = 1.4799.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](I)[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[Cu][C:28]#[N:29]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:28]#[N:29])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step E) (600 mg; 1.2 mmol) in tetrahydrofuran (15 mL) was added copper(I) iodide (137 mg, 0.72 mmol), tetrakis(triphenyphosphine)palladium(0) (416 mg, 0.36 mmol) and copper(I) cyanide (860 mg, 9.6 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 397 mg of the title compound as a crude yellow solid.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[CH3:20][C:21]1([CH3:27])[CH2:25][CH2:24][O:23][C:22]1=[O:26].C[Al](C)C.O>C1COCC1>[Br:19][C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([NH:2][C:22](=[O:26])[C:21]([CH3:27])([CH3:20])[CH2:25][CH2:24][OH:23])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(N)ccc12
Reactant: CC1(C)CCOC1=O
Agent: Br
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CCO)C(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 50 °C
Yield: 46 %

Procedure:
A mixture of 7-amino-4-bromo-9H-carbazole-1-carboxamide hydrobromide (Example 54-2, 500 mg, 1.299 mmol) and 3,3-dimethyldihydrofuran-2(3H)-one (222 mg, 1.948 mmol) in THF (10 mL) was treated with trimethylaluminum (2 M in toluene, 562 mg, 7.79 mmol) dropwise at rt. The mixture was heated at 50° C. for 1.5 h, cooled to rt and treated with water. The mixture was filtered through Celite and the solids were washed thoroughly with DCM and methanol. The filtrate was washed with water, dried and concentrated, and the residue was purified by column chromatography (eluting with a gradient from DCM to 10% ammonia-methanol-DCM) to provide 4-bromo-7-(4-hydroxy-2,2-dimethylbutanamido)-9H-carbazole-1-carboxamide as a yellow solid (250 mg, 46%). Mass spectrum m/z 418, 420 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[N:14][OH:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(C=NO)cc1
Yield: 98.3 %

Procedure:
A suspension of methyl 4-formylbenzoate (4.92 g), hydroxylamine hydrochloride (5.21 g) and sodium acetate (6.15 g) in ethanol (50 ml) was refluxed for 2 hours. The mixture was poured into water and extracted with ethyl acetate and the separated organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed under reduced pressure to give 4-methoxycarbonyl-benzaldehyde oxime (5.28 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC2CCCCC2)C1

Procedure:
tert-butyl (3S)-3-(cyclohexylamino)pyrrolidine-1-carboxylate was prepared by a method similar to that described in preparation 1 using tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate and cyclohexanone to yield the desired product, 5.9 g (82%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([NH:30][C:31](OC2C=CC=CC=2)=[O:32])[C:23](=[CH:28][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:31]([NH:30][C:22]2[CH:21]=[C:20]([Cl:19])[CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[O:32])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Yield: 100.9 %

Procedure:
1.0 g (3.66 mmol) of 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and 1.12 g (3.66 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 7 to obtain 1.79 g (yield 100%) of methyl 2-{[(4-t-butoxycarbonyl-3-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 1.57 (9H, s), 3.87 (3H, s), 7.14 (1H, d), 7.40-7.45 (2H, m), 7.85 (1H, d), 7.92 (1H, d), 8.32 (1H, d), 10.13 (1H, s), 10.82 (1H, s).