Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:47]([CH3:48])=[CH:46][C:39]([O:40][C@H:41]2[CH2:45][CH2:44][O:43][CH2:42]2)=[CH:38][C:37]=1[CH3:49]>>[CH3:49][C:37]1[CH:38]=[C:39]([O:40][C@H:41]2[CH2:45][CH2:44][O:43][CH2:42]2)[CH:46]=[C:47]([CH3:48])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(O[C@H]2CCOC2)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O[C@H]6CCOC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and (S)-3-(4-bromo-3,5-dimethylphenoxy)tetrahydrofuran following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 4): tR=1.89 min; Mass spectrum (ESI+): m/z=555 [M+Na]+.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH:15]1([NH:19][C:20](=[O:31])[NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH:15]1([NH:19][C:20](=[O:31])[NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:7]3[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]3[CH3:1])=[O:27])=[CH:29][CH:30]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccc(NC(=O)NC2CCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.6 %

Procedure:
To a solution of (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.10 g, 0.50 mmol) in N,N-dimethylformamide (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uronium hexafluorophosphate (0.190 g, 0.50 mmol, HATU), 4-(3-cyclobutylureido)benzoic acid (0.117 g, 0.50 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature for 20 hours and concentrated under vacuum. The residue was diluted with dichloromethane (15 mL) and washed with saturated ammonium chloride (aqueous) and brine. The organic layer was dried (sodium sulfate), filtered and concentrated under vacuum. The crude material was purified by column chromatography on silica (using a solvent gradient of dichloromethane/methanol) to afford the title compound (0.145 g) as a white solid.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH3:19][NH2:20]>C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:20][CH3:19])#[N:2]
Reactant: CSC(=NCCSCc1ncccc1O)NC#N
Reactant: CN
Solvent: CCO
Product: CN=C(NC#N)NCCSCc1ncccc1O
Reaction time: 2.5 h

Procedure:
A mixture of N-cyano-N'-[2-((3-hydroxy-2-pyridyl)-methylthio)ethyl]-S-methylisothiourea (4.8 g) and excess methylamine in ethanol was allowed to stand at room temperature for 2.5 hours. Following concentration under reduced pressure, the residue was chromatographed on a column of silica gel with ethyl acetate containing 15% isopropyl alcohol as eluant and recrystallisation from isopropyl alcohol-petroleum ether gave N-cyano-N'-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]-N"-methylguanidine (2.4 g), m.p. 146°-148°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][CH:18]([C:20](=O)[CH2:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH3:19]>>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:20]([CH:18]([CH3:19])[CH3:17])[C:21]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(C)C(=O)CC(=O)C(C)C
Product: CC(C)C(=O)c1c(C(C)C)nc2ccc(Br)cc2c1-c1ccccc1
Reaction time: 96 h
Yield: 46 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 2,6-dimethyl-3,5-heptanedione according to the method of example 1, except that the reaction time was of 96 h and the residue was purified by chromatography on aminated silica gel with heptane/ethyl acetate (85:15). Yield: 46%. MS: m/z=395/397 (M).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:31]1[N:36]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:28][N:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: CC(C)(C)C(N)=NO
Product: CC(C)(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 31.9 mg (0.275 mmol) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 1. Yield: 55.6 mg (46% of theory).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][N:7]([CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:8]([NH:10][CH2:11][CH:12]([O:21][Si](C(C)(C)C)(C)C)[CH2:13][N:14]1[CH2:19][CH2:18]N(C)[CH2:16][CH2:15]1)=[O:9])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].O1CC[CH2:44][CH2:43]1>>[C:1]([S:4][CH2:5][CH2:6][N:7]([CH2:29][CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:8]([NH:10][CH2:11][CH:12]([OH:21])[CH2:13][N:14]1[CH2:15][CH2:16][CH:43]([CH3:44])[CH2:18][CH2:19]1)=[O:9])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)SCCN(CCC1CCCCC1)C(=O)NCC(CN1CCN(C)CC1)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)SCCN(CCC1CCCCC1)C(=O)NCC(O)CN1CCC(C)CC1
Temperature: 25 °C

Procedure:
1-[2-(Acetylthio) ethyl]-3-[(2RS)-2-(t-butyldimethyl siloxy)-3-(4-methyl-1-piperazinyl)propyl]-1-(2-cyclohexylethyl) urea (Compound 3-19, 748 mg) was dissolved in anhydrous tetrahydrofuran (1.4 ml) in the nitrogen gas atmosphere, followed by the addition of a 1M solution of fluorinated tetra-n-butyl ammonium fluoride in tetrahydrofuran (1.45 ml) to the resulting solution with stirring at room temperature and stirring the mixture over 2.5 days. Saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. The resulting organic phase was washed with saturated aqueous solution of sodium hydrogen carbonate and then saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting oily product was purified by the silica gel column chromatography to thus give the title compound (Compound 5-1, 89 mg).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Br:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1O)[C:11]([O:13][CH3:14])=[O:12]>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[Cl:4])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(Cl)c([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
(I4B): Anhydrous DMF (242 ml) was cooled to −20° C. in a dry ice/acetone bath and the internal temperature was monitored carefully and maintained at or below this temperature. Neat oxalyl chloride (9.51 ml, 109 mmol) was then slowly added dropwise via addition funnel and the vessel was properly vented to allow the escape of gases generated. Following the addition, the cloudy-white suspension was stirred at −20° C. for 30 min. A solution containing methyl 3-bromo-4-hydroxy-5-nitrobenzoate (10 g, 36.2 mmol) in DMF (121 ml) was then added slowly, not allowing the internal temp to exceed −10° C. Following the addition, the suspension was warmed to rt and then heated to 100° C. for 2 h. The reaction was cooled to rt and stirred over weekend. The dark brown solution was poured into ice water and diluted with EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with water and brine, then dried over anhydrous sodium sulfate. Filtration and concentration afforded methyl 3-bromo-4-chloro-5-nitrobenzoate (10 g) as a yellow solid that was dried in vacuo overnight.
Reaction SMILES: C(O[C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:22][NH:23][C:24]([NH2:26])=[O:25].C[O-].[Mg+2].C[O-].CO>>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:4]([NH:26][C:24]([NH:23][CH3:22])=[O:25])=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 13.2 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (1.27 g, 4.36 mmol) and methyl urea (647 mg, 8.73 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 9.36 mL, 6.54 mmol) was refluxed at 100° C. for 8.5 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-nitro-phenyl)-propionyl]-3-methyl-urea (183.6 mg, 13.2%) as a white solid: mp 179-183° C.; EI-HRMS m/e calcd for C16H21N3O4(M+) 319.1532, found 319.1527.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH:21](O)[C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[CH:22]=[CH:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3(=[O:28])=[O:29])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)c2ccccc2C(O)CC1CCCN1CCN(c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=S1(=O)c2ccccc2C=CC1CCCN1CCN(c2ccc(F)cc2)CC1
Yield: 59.9 %

Procedure:
A suspension of 41.9 mg (0.1 mmol) of the Compound 23 in 10 ml of 3N hydrochloric acid aqueous solution was refluxed for 24 hours. The reaction mixture was cooled with ice, adjusted to pH 10 with a 5N aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by silica gel column chromatography (eluent:methanol:chloroform=1:99) to obtain 24 mg (yield: 60%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([F:26])[CH:25]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[O:6].Cl[C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([F:26])[CH:25]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[N:11]=[C:10]2[NH:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])=[O:6]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1cc(F)cc(F)c1)c1ccc2[nH]nc(NC(=O)C(F)(F)F)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc(F)cc(F)c1)c1ccc2c(c1)c(NC(=O)C(F)(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.3 %

Procedure:
N-[5-(3,5-Difluoro-benzoyl)-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide (19.11 g, 51.76 mmol) in dry dichloromethane (300 mL) was treated with chlorotriphenylmethane (14.72 g, 52.8 mmol) and triethylamine (14.55 mL, 103.5 mmol). After stirring at room temperature for two days, the reaction was washed with a solution of NH4Cl, dried and evaporated. Purification of the crude by chromatography over silica gel (DCM/MeOH) afforded 27.32 g of the title compound (86% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O>[CH3:27][O:26][C:24]([CH2:23][O:11][C:10](=[O:12])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1)=[O:25]
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)COC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 90.7 %

Procedure:
To a mixture of (4-nitrophenoxy)acetic acid 22 (150 g, 761.4 mmol) and triethyl-amine (85 g, 840 mmol) in acetone (750 ml) was added methyl chloroacetate (91.6 g, 844 mmol) drop wise and stirred under reflux for 8 hours. Solids were filtered off and poured onto cold 5% sodium bicarbonate solution (4 L). Crude 44 was filtered, dried and recrystallised from chloroform:hexane (1:6) to get pure 44 (186 g, 90.8%) as a white powder with an m.p. between 88-90° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][Zn+])=[CH:18][CH:17]=1.Cl>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]([F:24])([F:25])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1
Reactant: FC(F)(F)Oc1ccc(C[Zn+])cc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccc(OC(F)(F)F)cc2)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 92.3 %

Procedure:
To a solution of methyl 2-chloroisonicotinate (4.80 g, 28 mmol) and Pd(PPh3)4 (0.647 g, 0.56 mmol) in tetrahydrofuran (50 mL) under nitrogen in a dried flask was added a freshly prepared solution of (4-(trifluoromethoxy)benzyl)zinc(II) bromide (12.56 g, 39.20 mmol) in tetrahydrofuran (90 mL). The resulting bright yellow mixture was heated to 60° C. for 2 h 30 min, then cooled to room temperature. The reaction was quenched by the addition of 10% aqueous NH4Cl. It was diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was suspended in 50 mL MTBE and sonicated, then the yellow insolubles were filtered off and washed with MTBE. The volume of the filtrate was increased to ca. 150 mL, then 5 mL MeOH was added, followed by hydrogen chloride (4 M in dioxane) (7.00 mL, 28.00 mmol). A colorless precipitate formed, which then dissolved again. The solvents were evaporated. The residue was dissolved in ca. 15 mL DCM and then MTBE and heptanes were added. An oil had formed that was triturated and after a few minutes a solid started to form. It was sonicated and then stirred at room temperature for 20 min. The formed solid was collected and washed with MTBE and dried. The solid was dissolved in DCM and washed with 10% K2CO3. After phase separation, the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(4-(trifluoromethoxy)benzyl)isonicotinate (8.04 g, 92%) was isolated as a pale yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.22 (s, 2H), 7.11-7.17 (m, 2H), 7.24-7.31 (m, 2H), 7.67-7.72 (m, 2H), 8.68-8.72 (m, 1H). MS m/z 312 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=O)=[CH:13][CH:12]=3)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[S:37])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)N4CCCCC4)cc3c2c1C
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=S)N4CCCCC4)cc3c2c1C
Yield: 127.2 %

Procedure:
400 mg of 6-piperidinocarbonyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester is heated in 16 ml of toluene with 200 mg of Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithiaphosphetane-2,4-disulfide] for one hour to 100° C. Thereafter the mixture is combined with water and extracted twice with ethyl acetate. The ethyl acetate phase is dried, filtered, concentrated, and chromatographed over silica gel with methylene chloride/ethanol=10:1. Recrystallization of the corresponding fractions from ethanol/water yields 240 mg of 6-piperidinothiocarbonyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 225°-230° C.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[NH:20][CH2:21][C:22]1[C:23]([NH:32][CH2:33][CH3:34])=[CH:24][C:25]([N:28]([O:30][CH3:31])[CH3:29])=[N:26][CH:27]=1.CCN(CC)CC>>[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[N:20]1[CH2:21][C:22]2[CH:27]=[N:26][C:25]([N:28]([O:30][CH3:31])[CH3:29])=[CH:24][C:23]=2[N:32]([CH2:33][CH3:34])[C:2]1=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCNc1cc(N(C)OC)ncc1CNc1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: CCN(CC)CC
Product: CCN1C(=O)N(c2cc([N+](=O)[O-])c(F)cc2Cl)Cc2cnc(N(C)OC)cc21
Yield: 50.3 %

Procedure:
Diphosgene (3.1 g, 15.66 mmol), 5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine (4.3 g, 13.1 mmol) and Et3N (7 g, 65.2 mmol) were combined by the procedure of Example A4 to give 3-(2-chloro-4-fluoro-5-nitrophenyl)-1-ethyl-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2.7 g, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.55 (d, J=7.6 Hz, 1 H), 8.09 (d, J=11.2 Hz, 1 H), 8.00 (s, 1 H), 6.63 (s, 1 H), 4.91 (d, J=13.6 Hz, 1 H), 4.55 (d, J=13.6 Hz, 1 H), 3.93 (m, 2 H), 3.77 (s, 3 H), 3.20 (s, 3 H), 1.23 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 410.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([C:19]([OH:21])=O)=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([C:19]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:21])=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccncc1
Reactant: Cc1c(C(=O)O)ccc2c1SCCC2NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: Cc1c(C(=O)Nc2ccncc2)ccc2c1SCCC2NC(=O)OC(C)(C)C
Yield: 461.4 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using 4-(tert-butoxycarbonylamino)-8-methylthiochromane-7-carboxylic acid (400 mg), 4-aminopyridine (91.9 mg) and 2-chloro-1-methylpyridinium iodide (474 mg), the objective 4-(tert-butoxycarbonylamino)-8-methyl-N-(4-pyridyl)thiochromane-7-carboxamide (1.80 g) was obtained as colorless crystals.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH2:13][CH2:14][C:15](=[O:20])[C:16]([O:18][CH3:19])=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.O>C1COCC1>[OH:20][CH:15]([CH2:14][CH2:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(=O)CCc1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(O)CCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
NaBH4 (22 mg) was added portionwise to an ice cooled solution of methyl 4-(1-naphthyl)-2-oxobutyrate (obtained in Preparation 12) (252.5 mg) in THF(5 ml)-H2O (1 ml). After the addition was completed, the reaction mixture was stirred at ice-bath temperature for 30 minutes. Water (4 ml) was added, and the resulting mixture was stirred for several minutes and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel (5 g) column chromatography eluting with hexane/ethyl acetate (10:1) to give methyl 2-hydroxy-4-(1-naphthyl)butyrate (84.4 mg) as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]3[CH2:14][CH2:15][CH2:16][C@@H:9]23)=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26])#[CH:18]>>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[C:17]#[C:18][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]3[CH2:14][CH2:15][CH2:16][C@@H:9]23)=[N:6][CH:7]=1
Reactant: C#Cc1cc(F)ccc1F
Reactant: O=C1C[C@H]2CCC[C@H]2N1c1ccc(I)cn1
Product: O=C1C[C@H]2CCC[C@H]2N1c1ccc(C#Cc2cc(F)ccc2F)cn1
Yield: 98 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, step 7 using (3aR,6aR)-1-(5-iodopyridin-2-yl)hexahydro-cyclopenta[b]pyrrol-2(1H)-one (140 mg, 0.427 mmol) (Example 1, step 6) and 1-ethynyl-2,5-difluorobenzene to yield 142 mg (98%) of the title compound as a viscous light brown oil; MS: m/e=339.5 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=1>>[CH2:10]([O:9][C:7](=[O:8])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)[CH3:11]
Reactant: CCOC(=O)C(=O)c1cccs1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: CCOC(=O)C(=Nc1cccc(C(F)(F)F)c1)c1cccs1

Procedure:
Intermediate 7 was generated from ethyl thienylglyoxylate and 3-aminobenzo-trifluoride using general method G. The product was then purified on a column of silica gel (heptane/diisopropyl ether) and obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:7]=1[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[CH3:23].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:6]2[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:22]([CH3:23])=[N:8][C:7]=2[CH:9]=1
Reactant: CC=O
Reactant: CC(C)(C)Nc1ccc(-c2nc3ccccc3o2)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
To a solution of 2-(2-tert-butylaminoanilin-5-yl)benzoxazole (see Working Example 29-1) (45.0 mg, 0.160 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 235 μL, 0.480 mmol) and oxone (63.9 mg, 0.104 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (18.2 mg, 38% yield) as white crystals.