Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([CH2:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=O)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[CH2:30]([O:29][C:27]([C:25]1[NH:21][C:18]2[C:17]([CH:24]=1)=[CH:16][C:15]([O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]1)=[CH:20][CH:19]=2)=[O:28])[CH3:31]
Reactant: CCOC(=O)C(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc2[nH]1
Reaction time: 9 h

Procedure:
A mixture of 4-[3-(2-ethoxycarbonyl-2-oxo-ethyl)-4-nitro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 43, step 2, 42.25 g, 1.0 eq.), palladium on activated charcoal (10%, 2.111 g, 0.02 eq.) in ethanol (950 mL) was hydrogenated at 30° C. for 9 h. The mixture was filtered, washed with ethanol and evaporated to dryness. The product was recrystallized from ethyl acetate and heptane to yield 25.998 g (69%) as white crystals. MS (m/e): 388.2 (M, 45%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=4[Cl:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(C(F)(F)F)ccc4Cl)cc3CC[C@@H]12
Yield: 64.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-chloro-5-trifluoromethylphenylboronic acid (175 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 170 mg (64%) of the title compound as an oil. FDMS: m/e=407. α[D]589 =+49.42 (c=0.58, chloroform).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([C:14]4[CH:15]=[N:16][C:17]([NH:29][C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:18][C:19]=4[C:20]4[S:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=4)=[CH:11][CH:12]=3)[C:7](=[O:35])[C:6]([C:36](O)=[O:37])=[CH:5]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:72][O:73][CH2:74][CH2:75][NH2:76]>CN(C=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([C:14]4[CH:15]=[N:16][C:17]([NH:29][C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:18][C:19]=4[C:20]4[S:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=4)=[CH:11][CH:12]=3)[C:7](=[O:35])[C:6]([C:36]([NH:76][CH2:75][CH2:74][O:73][CH3:72])=[O:37])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COCCN
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C2CC2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)NCCOC)cn3C2CC2)cn1
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of 1-cyclopropyl-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 20, 80 mg, 0.15 mmol) in DMF (3 mL) was added HATU (112 mg, 0.29 mmol), DIEA (0.051 mL, 0.29 mmol) followed by 2-methoxyethanamine (22.11 mg, 0.29 mmol). After 1 h stirring, LC-MS shows completion of reaction. DMF removed under vacuum, and the residue was purified by ISCO column using MeOH—CH2Cl2 (0-20%) to give white solid (47.3 mg, 53.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CCO)c1
Yield: 98.8 %

Procedure:
Into a pressure bottle were added 2-(3-nitrophenyl)ethanol (3.0 g, 18 mmol) and methanol (100 mL) and 10% palladium on carbon (0.1 g, 0.08 mmol). The reaction mixture was hydrogenated at 45 psi overnight. The resultant mixture was filtered and concentrated to provide the desired product (2.44 g, 99%) as a white solid. LCMS for C8H12NO (M+H)+: m/z=138.1.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1)=[O:22]>>[CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([NH:19][C@@H:20]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[CH:46][CH:45]=2)[C:21]([N:23]([CH2:35][CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27][CH:26]=2)=[O:22])=[O:17])[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)NCC1(C(=O)O)CC1
Reactant: CCOC(CN(Cc1ccnc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Product: CCOC(CN(Cc1ccnc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C1(CNC(=O)NCc2ccccc2)CC1)OCC
Yield: 71.8 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 1-((3-benzylureido)methyl)cyclopropanecarboxylic acid (Compound VI-1) (174 mg, 0.35 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(quinolin-4-ylmethyl)propanamide (Compound IV-4) (173 mg, 0.7 mmol) and the obtained residue was purified by Purif silica gel column chromatography (eluent: n-hexane:ethylacetate=50:50 to 0:100) to obtain the title compound (182 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:33](=[O:41])[C:32]=1[C:42]#[N:43]>O1CCOCC1.CCOC(C)=O.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>[CH:38]1([CH2:37][N:34]2[CH:35]=[CH:36][C:31]([C:6]3[CH:5]=[CH:4][C:3]([NH:17][CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[C:2]([F:1])[CH:7]=3)=[C:32]([C:42]#[N:43])[C:33]2=[O:41])[CH2:39][CH2:40]1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(NC3CCOCC3)c(F)c2)ccn(CC2CC2)c1=O
Yield: 28.4 %

Procedure:
To a solution of intermediate 15 (0.8 g, 2.55 mmol) in 1,4-dioxane (3 ml) and a saturated solution of Na2CO3 (3 ml) was added intermediate 8 (0.58 g, 2.31 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.26 mg, 0.23 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 1 (0.241 g, 30%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[N:8]([CH2:12][CH:13]([CH3:15])[N:14]=3)[C:9]([CH3:11])=[N:10][C:5]=2[C:4]([CH3:16])=[N:3]1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:6]2[C:7]3[N:8]([CH:12]=[C:13]([CH3:15])[N:14]=3)[C:9]([CH3:11])=[N:10][C:5]=2[C:4]([CH3:16])=[N:3]1
Reactant: CC1=Nc2c(C)nn(C)c2C2=NC(C)CN12
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1C
Product: Cc1cn2c(C)nc3c(C)nn(C)c3c2n1
Yield: 50.7 %

Procedure:
A mixture of 2.4 g (0.011 mol) of 7,8-dihydro-1,3,5,8-tetramethyl-1H-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidine and 5.6 g (0.022 mol) of chloranil in 400 ml of xylene is stirred under reflux four hours. The warm mixture is extracted with two 150 ml portions of 1N sodium hydroxide. The organic layer is separated, filtered, dried over MgSO4, and evaporated in vacuo. The solid residue is stirred in ether to give 1.2 g (50%) of the title compound, mp 198°-200°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([CH2:12][O:13][CH3:14])[C:7]=1[O:8][CH2:9][C:10]#[N:11].I[CH3:23].[OH-].[K+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:23][N:15]([C:4]1[CH:5]=[C:6]([CH2:12][O:13][CH3:14])[C:7]([O:8][CH2:9][C:10]#[N:11])=[C:2]([Cl:1])[CH:3]=1)[C:16](=[O:21])[O:17][CH:18]([CH3:19])[CH3:20]
Reactant: COCc1cc(NC(=O)OC(C)C)cc(Cl)c1OCC#N
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCc1cc(N(C)C(=O)OC(C)C)cc(Cl)c1OCC#N
Temperature: 0 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
Isopropyl N-(3-chloro-4-cyanomethoxy-5-methoxymethylphenyl)carbamate (3.13 g) and iodomethane (4.30 g) were dissolved in tetrahydrofuran (10 ml). The resultant solution was dropwise added to a tetrahydrofuran solution (20 ml) containing potassium hydroxide (1.68 g) and tetra-n-butylammonium bromide (1.0 g). After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-methyl-N-(3-chloro-4-cyanomethoxy-5-methoxymethylphenyl)carbamate (Compound No. 41) (3.06 g) in a yield of 93.5%. nD22.0 1.5123.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[C:35]([O:39][C:40]([N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][C:46](B(O)O)=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:46]3[CH:45]=[C:44]4[C:49]([CH2:50][CH2:51][N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:43]4)=[CH:48][CH:47]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2C1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc5c(c3)CN(C(=O)OC(C)(C)C)CC5)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 65 °C

Procedure:
A stirring solution of Example 1F (0.1 g, 0.159 mmol) and 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-ylboronic acid (0.053 g, 0.191 mmol) in N,N-dimethylformamide (1.4 mL) was treated with saturated aqueous sodium bicarbonate (0.35 mL) followed by bis(triphenylphosphine)palladium(II) chloride (0.008 g, 0.012 mmol). The suspension was heated at 65° C. for 4 hours. The reaction was cooled to ambient temperature, and ethyl acetate and water were added. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel, eluting with a gradient of from 0% to 25% ethyl acetate in hexane, to provide the title compound. MS ESI(+) m/z 735.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](O)[C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([Cl:21])[C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)ccnc1O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: O=[N+]([O-])c1c(NCc2ccccc2)ccnc1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
4-benzylamino-3-nitro-pyridin-2-ol (6.15 g, 25.07 mmol) was suspended in 100 mL of acetonitrile then phosphorus oxychloride (12 mL, 125.40 mmol) was added followed by tetraethyl ammonium chloride (4.15 g, 25.07 mmol) and the mixture was stirred at 85° C. overnight. The solvent was removed in vacuo and the residue was suspended in water (300 mL) and extracted with dichloromethane (2×200 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give 5.9 g of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCCC1C([O-])=O.[BH4-]>CO>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: O=C([O-])C1CCCO1
Agent: [BH4-]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 75.0 g (0.226 mol) of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in amixture of 807 mL of methanol and 807 mL of tetrahydrofuranat -2° C., was added 13.17 g (0.348 mol, 1.54 equiv.) of solidsodium borohydride over one hundred minutes. The solventswere removed under reduced pressure at 40° C. and the residuedissolved in ethyl acetate (approx. 1 L). The solution waswashed sequentially with 1M potassium hydrogen sulfate,saturated sodium bicarbonate and then saturated sodiumchloride solution. After drying over anhydrous magnesiumsulfate and filtering, the solution was removed underreduced pressure. To the resulting oil was added hexane(approx. 1 L) and the mixture warmed to 60° C. with swirling.After cooling to room temperature, the solids werecollected and washed with 2 L of hexane. The resultingsolid was recrystallized from hot ethyl acetate and hexaneto afford 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150°-151° C. andM+Li+ =340.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([N+:19]([O-])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N.[Ni]>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([NH2:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccccc1
Agent: [Ni]
Agent: N
Product: NC1CN(Cc2ccccc2)CC1c1ccccc1
Reaction time: 12 h

Procedure:
To a stirred solution of (3S and R,4R and S)-1-benzyl-3-nitro-4-phenylpyrrolidine (100 g, 0.354 mol) in methanolic ammonia (1 L) was added Raney Ni (20 g) at room temperature in a 2.0 L hydrogenation flask. The reaction was hydrogenated at 100 psi for 12 h at room temperature. After completion of the reaction, the mixture was filtered through Celite and the filtrate was concentrated in vacuo to afford (3S and R,4R and S)-1-benzyl-4-phenylpyrrolidin-3-amine, which was carried onto the next step without further purification. MS ESI calc'd. For C12H20N2 [M+1]+ 253. found 253.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:24](=[O:27])[CH:25]=[CH:26][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:10]=3.O>C(O)(=O)C.Br>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:24](=[O:27])[CH:25]=[CH:26][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=3
Reactant: CC(C)(C)OC(=O)COc1cc2c(=O)ccn3c4cc(Br)ccc4c(c1)c23
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)COc1cc2c(=O)ccn3c4cc(Br)ccc4c(c1)c23
Yield: 92.1 %

Procedure:
9-bromo-2-t-butoxycarbonylmethyloxy-4H-pyrido[3,2,1-jk]carbazole-4-one (120 mg) produced in Example 118 was dissolved in acetic acid (5 ml) and 48% HBr (5 ml), and the solution was stirred at room temperature for 12 hours. The reaction mixture was poured into water and the crystals precipitated were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (96 mg, 92%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16]CC)=O)[C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=2[F:39])=[O:27])=[CH:21][CH:20]=1)(=[O:8])[NH2:7]>>[F:39][C:30]1[CH:31]=[CH:32][C:33]([C:35]([F:36])([F:37])[F:38])=[CH:34][C:29]=1[NH:28][C:26](=[O:27])[NH:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[C:11]([C:14]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:16])=[CH:12][NH:13][C:9]=2[C:6]([NH2:7])=[O:8])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reactant: C1CCNC1
Product: NC(=O)c1[nH]cc(C(=O)N2CCCC2)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1

Procedure:
The process is performed in a manner similar to that described in Example 39 but starting with pyrrolidine and ethyl 5-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxylate. After a similar work-up, 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-4-(pyrrolidine-1-carbonyl)-1H-pyrrole-2-carboxamide is obtained; ES+: m/z=504 [M+H]+.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:13][NH2:14]>C(O)C>[C:1]([NH:13][NH2:14])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml 3-neck flask were added 40 ml of ethanol and 6 g of ethyl benzoate, to which 12.5 g of 85% hydrazine hydrate was added slowly and dropwise with stirring. After the addition was completed, the mixture was heated under reflux for 8 hours and then cooled to room temperature. The solvent was distilled under reduced pressure and water was added. The solid was precipitated. The mixture was allowed to stand for 30 min until the solid was fully precipitated, which was filtrated and washed with water. Recrystallization with anhydrous ethanol gave benzoyl hydrazine.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:30])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:18]([CH:20]=[CH2:21])[CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.ClCCl>[CH2:3]([O:5][C:6](=[O:30])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:18]([CH:20]=[CH2:21])[CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: C=Cc1cc(CC(C(=O)OCC)C(=O)OCC)cnc1NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1cc(CC(C(=O)O)C(=O)OCC)cnc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.1 %

Procedure:
A solution of KOH (0.71 g, 12.6 mmol, 85%) in ethanol (10 ml) was added to a solution of 2-(6-tert-butoxycarbonylamino-5-vinyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (4.30 g, 11.0 mmol) in ethanol (25 ml) and dichloromethane (10 ml) at 0° C. The mixture was stirred for 6 h at room temperature. The solvent was evaporated in vacuo and the residue dissolved in water. The aqueous layer was washed with ether, acidified to pH 4 by 1 M HCl and extracted with dichloromethane. The organic layer was washed with water and brine and dried. Filtration and concentration under reduced pressure followed by flash chromatography (10% MeOH in CH2Cl2) gave 2-(6tert-butoxycarbonylamino5-vinyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (3.05 g, 76%).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=[O:9].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:10]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:4][CH3:3])=[C:12]([O:13][CH3:14])[CH:11]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(Br)c(C=O)cc1OC
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A solution of bromine (0.96 g) in acetic acid (10 ml) was dropped into a solution of 3,4-dimethoxybenzaldehyde (1.0 g) in acetic acid (4 ml) and the mixture was stirred for three hours. Sodium thiosulfate was added to the reaction mixture, then sodium bicarbonate was added thereto and the mixture was filtered. The crude crystals collected by the filtration were recrystallized from chloroform-ether to give the title compound (0.83 g, 56%). The peaks of this compound in 1H-NMR (400 MHz, CDCl3) were as follows.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH3:14][CH:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:19][CH:15]([CH3:14])[CH:16]([CH3:18])[CH3:17])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: CC(C)C(C)N
Product: CC(C)C(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 72 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g, 1.94 mmol) in 1,2-dimethylpropylamine (5 ml) was stirred for 48 h at 100° C in a sealed flask. The cooled mixture was concentrated in vacuo and the residue was stirred with water (20 ml) followed by adjustment to pH 2 with 4M hydrochloric acid. The initially formed gummy product crystallised by stirring the mixture for about 2 h at 0° C. The precipitate was isolated by filtration, washed with water, and recrystallised from ethyl acetate/methanol followed by drying in vacuo at 60° C. over night to give 0.43 g (72%) of the pure title compound.