Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1.O>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:9]2[C:10]3[C:15](=[N:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:28]=[CH:29][CH:30]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3cccnc3c2=O)cc1C
Reaction time: 0.08 h
Yield: 12.2 %

Procedure:
To a solution of 0.060 g (0.216 mmol) of 3-(3,4-Dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one in 2.0 mL of N,N-dimethylformamide was added 10.4 mg (0.259 mmol, 60% dispersion in oil) of sodium hydride and the reaction was stirred for 5 min. 65 mg (0.259 mmol) of 2-bromo-6-bromomethyl-pyridine was added and the reaction was stirred at room temperature for 3 h. Water was added and the solid collected by filtration. The crude brown solid was purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 11.8 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one as an off white solid.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].I[CH3:25]>COCCOC>[CH2:20]([O:19][C:17]([N:15]1[CH2:14][CH2:13][C:10]2[N:11]([CH3:25])[C:12]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]=2[CH2:16]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)N1CCc2[nH]c3c([N+](=O)[O-])cccc3c2C1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CCOC(=O)N1CCc2c(c3cccc([N+](=O)[O-])c3n2C)C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 108.9 %

Procedure:
Ethyl 6-nitro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (0.33 g, 1.12 mmol) was combined with KOH (0.31 g, 5.6 mmol) and iodomethane (1.3 g, 8.96 mmol) in ethylene glycol dimethyl ether (5.6 mL) and stirred at 90° C. for 16 h. The inorganic solid was filtered and the filtrate evaporated to give ethyl-5-methyl-6-nitro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (0.37 g) as an orange oil in near quantitative yield. 1H NMR (CDCl3, 300 MHz) δ 7.74 (d, 1H, J=7.7 Hz), 7.67 (d, 1H, J=7.7 Hz), 7.12 (t, 1H, J=8.0 Hz), 4.70 (s, 2H), 4.22 (q, 2H, J=7.0 Hz), 3.91 (br. s, 2H), 3.62 (s, 3H), 2.84 (t, 2H, J=5.5 Hz), 1.30 (t, 3H, J=7.0 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[NH2:24][C:25]1[C:26]([C:36]([NH2:38])=[O:37])=[N:27][N:28]([CH2:32][CH2:33][O:34][CH3:35])[C:29]=1[CH2:30][CH3:31]>C(OCC)(=O)C>[C:36]([C:26]1[C:25]([NH:24][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]3)(=[O:14])=[O:15])[CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2])=[C:29]([CH2:30][CH3:31])[N:28]([CH2:32][CH2:33][O:34][CH3:35])[N:27]=1)(=[O:37])[NH2:38]
Reactant: CCc1c(N)c(C(N)=O)nn1CCOC
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(CCOC)c1CC
Temperature: 45 °C
Reaction time: 0.67 h
Yield: 14.5 %

Procedure:
2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (2.31 kg, 6.73 Mol) was suspended in ethyl acetate (16.2 L) and 1,1-carbonyldimidazole (1.09 kg, 6.73 Mol) was added at room temperature. The reaction mixture was heated at 45° C. for 40 minutes and then the reaction was stirred for a further 40 minutes at reflux. After cooling to ambient temperature 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (1.5 kg, 7.06 Mol) was added to the cooled mixture, and the reaction stirred for a further 15 hours under reflux. The mixture was cooled filtered and the filter cake was washed with 90% water/10% ethyl acetate, (2 mL/g) to afford N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide as an off white crystalline solid, 3.16 kg, 88%. m.p.=156° C. Found: C, 51.33; H, 6.56; N, 18.36. C23H35N7O6S requires C, 51.40; H, 6.53; N, 18.25%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:22])[N:20]=2)[CH:17]=1
Reactant: Cc1cccc(Cl)c1CN
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: Cc1cccc(Cl)c1CNC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2-chloro-6-methylphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30]>CN(C)C=O>[OH:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCCOCCO)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
The crude benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (2.83 g, 10.2 mmol) from the previous reaction was dissolved into dimethylformamide (60 mL). Cesium carbonate (6.65 g, 2 equiv, 20.4 mmol) was added in one portion to the solution to give a suspension followed by 2-(2-chloroethoxy)ethanol (1.39 g, 11.2 mmol). The flask was sealed with a septum and vigorously stirred at 50° C. under nitrogen atmosphere for 16 hours. The suspension was concentrated to an oily solid residue. This material was mixed with ethyl acetate (200 mL) and water (50 mL). The layers were separated and the organic layer was washed with brine (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a yellow oil. The crude oil was used without purification (2.23 g, 64.3%). LRMS (ESI/APCI) m/z 342 [M+H]+.
Reaction SMILES: O[CH2:2][C@H:3]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:4][C:5](=[O:17])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[N:8]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:16][C:9]1[N:8]=[C:7]([N:6]2[C:5](=[O:17])[CH2:4][C@@H:3]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:2]2)[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1nc(NC(=O)C[C@H](CO)NC(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1nc(N2C[C@H](NC(=O)OCc3ccccc3)CC2=O)ccc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 2c from benzyl (R)-[1-hydroxymethyl-2-(6-methyl-5-nitro-pyridin-2-yl-carbamoyl)-ethyl]-carbamate with di-tert.-butyl azodicarboxylate and tributylphosphine in THF and subsequent purification by reversed-phase chromatography.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]2)=[C:22]([C:32]([F:35])([F:34])[F:33])[CH:21]=1)=[O:18]>>[CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:37]3[CH:36]=[C:16]([CH:15]=[CH:14][C:38]=3[CH3:39])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]4)=[C:22]([C:32]([F:33])([F:34])[F:35])[CH:21]=3)=[O:18])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(I)c3)cc2C(F)(F)F)cn1
Reactant: C#Cc1ccc(NC2CC2)nn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(C#Cc4ccc(NC5CC5)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide (as prepared above) in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 125-126° C.; 1H NMR (300 MHz, CDCl3) δ: 9.94 (1H, s), 8.34 (1H, s), 8.20-8.23 (1H, d, J=8.7 Hz), 8.02 (1H, s), 7.86-7.89 (1H, d, J=8.1 Hz), 7.53 (1H, s), 7.39-7.42 (1H, d, J=9.0 Hz), 7.30-7.32 (2H, m), 7.02-7.05 (1H, d, J=9.2 Hz), 6.80 (1H, s), 6.02 (1H, s), 2.58 (1H, m), 2.48 (3H, s), 2.29 (3H, s), 0.87 (2H, m), 0.64 (2H, brs). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C28H25F3N6O: 259.1015. found: 259.1023.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:3]1.[CH3:18][Si:19]([CH2:22][Mg]Cl)([CH3:21])[CH3:20]>CCOCC>[CH3:18][Si:19]([CH2:22][C:11]1([OH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:3][C:2]1=[O:1])([CH3:21])[CH3:20]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: CCOC(=O)C1CCCCCCC(=O)C(=O)N1
Solvent: CCOCC
Product: CCOC(=O)C1CCCCCCC(O)(C[Si](C)(C)C)C(=O)N1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Ethyl 2,3-di-oxo-1-azacyclodecane-10-carboxylate (5.02 g, 20.81 mmol) is dissolved in ether (50 mL), and cooled to 0° C. Trimethylsilylmethylmagnesium chloride (42.0 mL of a 1.0M solution in ether, 42.0 mmol) is added dropwise, the reaction is stirred at 0° C. for 20 minutes, and then heated to reflux overnight. The reaction is quenched with saturated ammonium chloride, and extracted several times with ethyl acetate. The combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give separately the two diastereomers of ethyl 3-(trimethylsilylmethyl)-3-hydroxy-2-oxo-1-azacyclodecane-10-carboxylate; major isomer, m.p. 129°-130° C.; minor isomer, m.p. 175°-177° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:30])([C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[Br:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([F:30])([F:13])[C:20]([F:28])([F:29])[C:21]([F:26])([F:27])[C:22]([F:23])([F:24])[F:25])=[CH:34][CH:33]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCOc1ccc(Br)cc1

Procedure:
A solution of diethyl azodicarboxylate (3.5 g, 20 mmol) in dry diethyl ether (20 cm3) was added dropwise into a stirred solution of 5,5,6,6,7,7,8,8,8-nonafluorooctan-1-ol (Preparation 2A, 5.8 g, 20 mmol), 4-bromophenol (3.5 g, 20 mmol) and triphenylphosphine (5.3 g, 20 mmol) in dry diethyl ether (50 cm3) at room temperature.
Reaction SMILES: [S:1]([C:5]1[CH:20]=[CH:19][C:8]([NH:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[C:21]([CH2:23][C:24](OCC)=[O:25])#[N:22].C([O-])(=O)C.[NH4+]>>[NH4+:9].[C:21]([C:23]1[C:24](=[O:25])[N:9]([C:8]2[CH:19]=[CH:20][C:5]([S:1]([OH:4])(=[O:3])=[O:2])=[CH:6][CH:7]=2)[CH2:10][C:11]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:22]
Reactant: CCOC(=O)CC#N
Reactant: O=C(CNc1ccc(S(=O)(=O)O)cc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N#CC1=C(c2ccccc2)CN(c2ccc(S(=O)(=O)O)cc2)C1=O
Temperature: 130 °C
Reaction time: 0.42 h
Yield: 104 %

Procedure:
A mixture of 14.5 grams (50 mmol) of 2-(4-sulfoanilino)acetophenone, 45.2 grams (0.4 mol) of ethyl cyanoacetate and 12.2 grams (0.2 mol) of ammonium acetate in a reaction flask fitted with distillation head was stirred and placed in an oil bath pre-heated to 130° C. At an internal temperature of 60° C. the reaction mixture became easily stirrable. Distillate began to collect at 95° C. and the reaction was brought to an internal temperature of 115° C. After 25 minutes the product mixture had become a thick slurry. The product mixture was then cooled, diluted with 100 mL of ethanol and stirred. The tan-yellow product was collected by filtration and washed with ethanol, acetone and ligroin to give a crude weight of product of 10.1 grams. The product was recrystallized from glacial acetic acid to give 9.35 grams (26 mmol, 52% yield) of product as a yellow powder, m. p.=275°-300° C. (decomposes). Elemental Analysis: Calculated: C=57.13, H=4.23, N =11.76, S=8.97; Found: C=57.07, H=4.31, N=11.66, S=8.40.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[N+:16]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[CH:13][C:12]=1[OH:15])([O-:18])=[O:17]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Yield: 70.5 %

Procedure:
To 20 g (0.1 mole) of 4-phenylmethoxy-phenol in 200 ml acetic acid were added, dropwise at room temperature, 7.26 ml of nitric acid (d=1.4, 0.105 mole). 2 Hours after completion of the addition the reaction medium was poured onto cold water and extracted twice with 250 ml of methylene chloride. The organic phase was washed twice with 200 ml of water and dried over sodium sulfate. Then the solvent was evaporated and the residue flash chromatographed using ethyl acetate/heptane 30/70 as eluting solvent to give 17.3 g (Yield=70.6%) of 2-nitro-4-phenylmethoxy-phenol.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:3].C[Si](C)(C)[N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19]>C1C=CC=CC=1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[O:3])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: O=C(Cl)Oc1ccc(F)cc1
Solvent: c1ccccc1
Product: O=C1CCCN1C(=O)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a solution of 4-fluorophenyl chloroformate (3.55 g, 20.0 mmol) in anhydrous benzene (10 ml ) was added a solution of 1-trimethylsilyl-2-pyrrolidinone (3.46 g, 22.0 mmol) in anhydrous benzene (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to dryness to give a solid material. Recrystallization from 2-propanol afforded 2.24 g of colorless prisms. Yield 46.9%
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:5]([OH:7])=O)[CH3:2].[CH2:19]([O:26][C:27](=[O:39])/[N:28]=[C:29](\[NH2:38])/[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:39])/[N:28]=[C:29](\[NH2:38])/[C:30]1[CH:31]=[CH:32][C:33]([CH2:36][NH:37][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[N:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([CH3:17])=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:34][CH:35]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccc(/C(N)=N/C(=O)OCc2ccccc2)cc1
Reactant: CCOC(C(=O)O)N1Cc2ccc(C)cc2C1=O
Product: CCOC(C(=O)NCc1ccc(/C(N)=N/C(=O)OCc2ccccc2)cc1)N1Cc2ccc(C)cc2C1=O

Procedure:
According to general procedure C, (RS)-ethoxy-(6-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetic acid was reacted with [1-amino-1-(4-aminomethyl-phenyl)-meth-(Z)-ylidene]-carbamic acid benzyl ester to give (RS)-[1-amino-1-(4-{[2-ethoxy-2-(6-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-methyl}-phenyl)-meth-(Z)-ylidene]-carbamic acid benzyl ester as light yellow foam, MS 515.5 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:11]=2[CH2:35][C:36]([CH3:43])([CH3:42])[C:37]([O:39]CC)=[O:38])=[O:9])=[CH:4][CH:3]=1.CC(O)=O>C1COCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:29](=[O:34])[C:30]([CH3:32])([CH3:33])[CH3:31])[C:11]=2[CH2:35][C:36]([CH3:43])([CH3:42])[C:37]([OH:39])=[O:38])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3cccc(OC)n3)ccn2c1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cccc(COc2ccn3c(C(=O)c4ccc(Cl)cc4)c(CC(C)(C)C(=O)O)c(C(=O)C(C)(C)C)c3c2)n1
Yield: 99.8 %

Procedure:
A solution of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-[(6-methoxypyridin-2-yl)methoxy]indolizin-2-yl}-2,2-dimethylpropanoate (20 mg, 0.033 mmol) in THF (2.0 mL) and 10M aqueous NaOH (1.5 mL) is heated at 45° C. for 1.5 h. The mixture is then acidified with HOAc, concentrated in vacuo, and partitioned between EtOAc and water. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo to give the title compound (19 mg, quant).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1.[CH2:15](Br)[CH:16]=[CH2:17]>CN(C)C=O.[Cl-].[Na+].O>[CH2:17]([N:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:11]1=[O:12])[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)C(=O)NCCC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCCc2ccc(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A solution of 8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (10.0 g, 0.052 mol) in N,N-dimethylformamide (30 mL) and allylbromide (23 mL, 0.260 mL) was treated with Nail (60% by wt. dispersion in oil, 2.50 g, 0.063 mol) and the resulting grey suspension stirred at room temperature under an atmosphere of argon. Gas evolution was noted. After 15 minutes, the solution was diluted with brine and partitioned between ethyl acetate and brine. The combined organic layers were concentrated in vacuo and purified by chromatography over silica gel eluting with a gradient of hexane to 1:1 ethyl acetate/hexane to yield 8 g (83%) of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCc1ccccc1

Procedure:
In 2.3 ml of methylene chloride was added 0.470 g of 5-phenylvaleric acid, to which were added at ambient temperature 0.287 ml of thionyl chloride and 0.020 ml of N,N-dimethylformamide. After a reaction at the same temperature as above for 4 hours, the reaction mixture was concentrated under reduced pressure, 5.0 ml of toluene was added and the resulting mixture was further concentrated under reduced pressure. Thus, 0.510 g of 5-phenylvaleric acid chloride was obtained as a light yellow oily product.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[F:6][C:7]([F:25])([F:24])[C:8]([N:10]([CH2:17][P:18]([O:22]Cl)([O:20]Cl)=[O:19])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9]>CCOCC>[F:6][C:7]([F:25])([F:24])[C:8]([N:10]([CH2:17][P:18]([OH:22])([O:20][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:19])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9]
Reactant: CCCCN
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: CCCCN(CCCC)OP(=O)(O)CN(CC(=O)OCC)C(=O)C(F)(F)F
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution of n-butylamine (3.1 g, 0.0423 mole) in 40 ml. of ether was added dropwise with stirring ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (3.3 g, 0.01 mole) in 50 ml. of ether. The reaction mixture was stirred for 21/2 hours, then filtered and the filtrate was concentrated in vacuo to give a light yellow viscous oil. This oil was dissolved in petroleum ether, washed three times with water, dried over MgSO4, and concentrated in vacuo to give 3.3 g of ethyl N-trifluoroacetyl-N-(dibutylaminophosphonomethyl)glycinate, ND =1.4429.
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][Mg]Br>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1
Reactant: Clc1cccc(C[Mg]Br)c1
Reactant: COC(=O)c1cc2c([nH]1)C(=O)CC2
Product: COC(=O)c1cc2c([nH]1)C(Cc1cccc(Cl)c1)CC2

Procedure:
The title compound was synthesized in two steps. Methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (447 mg, 2.5 mmol) was reacted with 3-chlorobenzylmagnesium bromide (0.25 M in hexanes, 25 mL, 6.3 mmol) according to General Procedure 3 to give the exocyclic olefin-containing compound (E)-methyl 6-(3-chlorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6, and was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 143 mg.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:9]=2[CH:8]=1)=[O:6]>CO.O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C@H:10]1[C:9]2[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)=[O:26]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
LiOH (4 equiv.) was added to a suspension of (8R)-8-[(2-chloro-benzoyl)amino]-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (B-06) in methanol and water and the reaction mixture was stirred at 25° C. for 2.5 hours. (According to TLC control: educt still present) The reaction mixture was topped up with 2 equiv. of LiOH and stirred at 25° C. overnight. Methanol was distilled off and the aqueous residue was diluted with ether and dist. water. The phases were separated and the aqueous phase was acidified with 1N HCl. Finally, the aqueous phase was extracted 4× with ethyl acetate (spot test) and the extract was dried over sodium sulfate and concentrated. Yield:81.4%.
Reaction SMILES: [F:1][C:2]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:21])([F:1])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2ccccc12
Product: Fc1ccc(C(F)(F)c2nc(Cl)c3ccccc3n2)nc1
Temperature: 95 °C
Yield: 82 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol from Example 2 Step D (1.82 g, 6.25 mmol) was added phosphorousoxychloride (20 mL) and the mixture was heated at 95° C. for 3 h. The mixture was concentrated under reduced pressure and then toluene (20 mL) was added and evaporated. The residue was dissolved in EtOAc and washed with saturated NaHCO3 (1×) and brine (1×), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with 10-80% EtOAc/hexanes to afford 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline (1.59 g, 82%). 1H NMR (300 MHz, DMSO-d6) δ 8.61 (d, J=2.6 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.17-8.29 (m, 2H), 8.06-8.15 (m, 1H), 7.96-8.06 (m, 2H); LC-MS (ESI) m/z 310 (M+H)+.