Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:16])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reaction time: 2.5 h

Procedure:
Combine 3,4-dichlorophenyl acetic acid (9 g, 44 mmol) and dichloromethane (100 ml). Add dropwise a solution of oxalyl chloride (30 ml, 2 M, 60 mmol) in dichloromethane. Add dimethylformamide (6 drops). After 2.5 hours, evaporate in vacuo to give a residue, twice had dichloromethane and evaporate in vacuo to give the title compound which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:14][O:15][CH3:16])[C:3]=1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1.O1CCCC1.O.NN>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.CO>[Cl:1][C:2]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:14][O:15][CH3:16])[C:3]=1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1
Reactant: COCn1c(-c2nccs2)c(Cl)c2cccc([N+](=O)[O-])c21
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCn1c(-c2nccs2)c(Cl)c2cccc(N)c21
Yield: 91.8 %

Procedure:
A mixture of 3-chloro-1-(methoxymethyl)-7-nitro-2-(1,3-thiazol-2-yl)-1H-indole (0.30 g), iron(III) chloride hexahydrate (15 mg), activated carbon (0.15 g), tetrahydrofuran (6 mL) and methanol (6 mL) was heated under reflux for 20 min. To the reaction mixture was added hydrazine monohydrate (0.27 g) while heating under reflux. The reaction mixture was heated under reflux for 2 hr, filtrated, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (0.25 g, yield 91%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2].[CH3:41]I>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:20]([CH:25]([C:26]2[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=2)[CH3:41])[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Solvent: C1CCOC1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N(C(=O)OC)C(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a pre-dried flask under nitrogen atmosphere was added cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.200 g, 0.346 mmol) and tetrahydrofuran (2 mL). The solution was cooled to -78° C. and a 1.83 M solution of n-butyl lithiumin hexanes (0.23 g, 0.41 mmol) was added. The reaction was stirred at -78° C. for 45 min, then methyl iodide (0.026 mL, 0.41 mmol) was added and the reaction was warmed to 0° C. and stirred for 90 min. The reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give crude product. Purification by silica gel chromatography using 20% ethyl acetate/hexanes, followed by 70% ether/hexanes as eluent afforded the desired methylated product. MS m/z 593 (M+ +H); 1H NMR (CDCl3) δ 7.85 (bs, 1H), 7.8 (bs, 2H), 7.05 (bs, 1H), 6.5 (bs, 1H), 3.9 (s, 3H), 3.85 (s, 3H), 1.65 (d, 1.5H, J=7 Hz), 1.05 (d, 1.5H, J=7.0 Hz).
Reaction SMILES: CC1C=CC(S(OCC2CC3C=C(F)C=C(C4C=CC=CC=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:33]([CH2:36][CH:37]1[CH2:41][C:40]2[CH:42]=[C:43]([F:52])[CH:44]=[C:45]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:39]=2[O:38]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[F:52][C:43]1[CH:44]=[C:45]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:39]2[O:38][CH:37]([CH2:36][NH2:33])[CH2:41][C:40]=2[CH:42]=1
Reactant: [N-]=[N+]=NCC1Cc2cc(F)cc(-c3ccccc3)c2O1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: NCC1Cc2cc(F)cc(-c3ccccc3)c2O1
Yield: 68 %

Procedure:
Treatment of (±)-(5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.76 mmol) with sodium azide (0.979 g, 15.06 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.101 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.719 g (68%) of (±)-1-(5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 255-260° C.; Anal. calcd. for C15H14FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 64.16; H, 5.54; N, 4.73.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH:27]=[N:26][C:25]([NH2:28])=[N:24]1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH:27]=[N:26][C:25]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:24]1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ncn(-c2ccccc2Cl)n1
Product: Cc1cn(-c2ccc(Nc3ncn(-c4ccccc4Cl)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(2-chloro-phenyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless solid (Yield=27%). MS ISP (m/e): 374.3 (100) [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]Br>C(O)(=O)C>[Br:13][C:9]1[C:10]([OH:12])=[CH:11][C:2]([F:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(O)cc1F
Temperature: 45 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
To a solution of 66.43A (2.03 g, 11.9 mmol) in acetic acid (65 mL) was added a pre-mixed solution of bromine (0.67 mL, 13.1 mmol) in acetic acid (10 mL). The mixture was stirred at 45° C. and monitored with TLC and LC-MS. After 18 hours, the reaction mixture was concentrated under reduced pressure. Brine was added to the residue, and the mixture was extracted three times with EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to provide 66.43B as a white solid (2.12 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1H, d, J=7.4 Hz), 6.82 (1H, d, J=11.3 Hz), 6.04 (1H, s), 3.92 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[BH4-].[Na+]>CO.C(OCC)(=O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[F:11][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([F:1])[C:3]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
Nickel chloride hexahydrate (2.32 g, 9.83 mmol) was added to a solution of 4-(2,6-difluoro-4-nitrophenyl)morpholine (1.2 g, 4.92 mmol), obtained in Preparation 1, in methanol (50 mL). NaBH4 (749 mg, 19.6 mmol) was added to the reaction mixture in portions and was allowed to stir at room temperature for 0.5 h. It was diluted with ethyl acetate (100 mL) and the organic portion was washed with water (60 mL×2) followed by brine (50 mL) and dried over sodium sulfate. Evaporation of the volatiles produced the title compound (0.95 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][CH2:11][NH:12][CH:13]([C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.[C:38](O)(=[O:40])[CH3:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH2:9][CH2:10][CH2:11][N:12]([CH:13]([C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:38](=[O:40])[CH3:39]
Reactant: CC(=O)O
Reactant: Cc1cccc(C)c1C(CN1CCCCC1)NCCCc1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(CCCc1c(F)cccc1F)C(CN1CCCCC1)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
150 mg (0.39 mmol) of [3-(2,6-difluorophenyl)propyl]-[1-(2,6-dimethylphenyl)-2-piperidin-1-ylethyl]amine (corresponds to Example 35) is placed in 3 ml of THF. Then 0.07 ml of DIPEA and 0.02 ml (0.39 mmol) of acetic acid are added; and finally 124.6 mg (0.39 mmol) of TBTU are added. The mixture is then stirred for 6 hours at room temperature, the solvent is eliminated, ethyl acetate and saturated NaHCO3 solution are added, and the resulting mixture is stirred for 15 minutes. The phases are separated and the organic phase is washed twice more with NaHCO3 solution and twice with saturated NaCl solution. The organic phase is dried and evaporated down and the residue is purified by flash chromatography (cyclohexane/ethyl acetate 7:3). MS: m/z 429 [(M+H)+].
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>ClCCl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[C:27]([S:31]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:32])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h

Procedure:
To tert-butyl piperazine-1-carboxylate (1.39 g, 7.46 mmol) and diisopropylethylamine (1.955 mL, 11.19 mmol) in dichloromethane (10 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.196 mL, 7.46 mmol) dropwise. The reaction was stirred overnight. Thin layer chromatography indicated formation of a new product (hexanes/ethyl acetate 1:1). The reaction was diluted with dichloromethane (50 mL), washed with 1 N HCl (50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated to give the title compound.
Reaction SMILES: [C:1]([OH:6])(=O)[C@@H:2]([CH3:4])[OH:3].[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][C@H:34]([CH3:38])[CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][C@H:34]([CH3:38])[CH2:35][N:36]([CH3:37])[C:1](=[O:6])[C@H:2]([OH:3])[CH3:4])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C[C@@H](O)C(=O)O
Product: C[C@H](CN(C)C(=O)[C@@H](C)O)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 26 %

Procedure:
The procedure described in Example 1 was repeated using D-(−)-lactic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the title compound as a white solid in 26% yield; NMR spectrum (DMSO-d6 373K) 1.15 (d, 3H), 1.44 (d, 3H), 2.97 (s, 3H), 3.16 (m, 1H), 4.05 (dd, 1H), 4.43 (m, 1H), 5.16 (m, 1H), 5.27 (s, 2H), 7.23 (m, 2H), 7.35 (m, 2H), 7.59 (m, 2H), 7.70 (t, 1H), 7.84 (dt, 1H), 8.09 (d, 1H), 8.47 (s, 1H), 8.59 (d, 1H), 9.90 (s, 1H); Mass spectrum MH+ 522.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([CH3:11])=[CH:8][C:7](=[O:12])[NH:6][C:5]=2[N:4]([CH3:13])[N:3]=1.CCN(C(C)C)C(C)C.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:8][C:9]=2[CH3:11])[N:4]([CH3:13])[N:3]=1
Reactant: Cc1cc(=O)[nH]c2c1c(Cl)nn2C
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C)c2c(Cl)nn(C)c2n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
3-chloro-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (720 mg, 3.64 mmol) was dissolved in DMF (5 ml) at rt. Then, DIPEA (1.04 g, 8.0 mmol) and ethyl 2-bromoacetate (0.60 ml, 5.5 mmol) were added and the mixture heated at 90° C. After 1 h, the mixture was cooled to rt, the solvent removed under reduced pressure and the residue purified by column chromatography (eluent 70% hexane in EtOAc) to yield 664 mg (64%) of the title compound. [1H-NMR (DMSO-d6, 400 MHz) δ 6.67 (s, 1H), 4.98 (s, 2H) 4.17 (q, 2H), 3.84 (s, 3H), 2.62 (s, 3H), 1.19 (t, 3H); HPLC-MS RtJ=1.13 min; [M+H]+=284.0, 286.0
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=S>>[N:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:5][C:18]=1[NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1ccccc1N=C=S
Reactant: NCc1ccccc1N
Product: Cc1ccccc1NC1=Nc2ccccc2CN1

Procedure:
The title compound (MS: m/e=238.3 [M+H+]) was prepared in analogy to example 1 from 2-aminobenzylamine and 2-methylphenylisothiocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)=[C:22]=[O:23]>CN(C=O)C>[C:27]1([CH3:30])[CH:28]=[CH:29][C:24]([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])=[CH:25][CH:26]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C)cc4)CC3)c2cc1OC
Yield: 84.2 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (20 mg, 0.0733 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-isocyanato-4-methyl-benzene (15 mg, 0.113 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a brown solid (25.1 mg, 84%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.26-7.21 (m, 3H), 7.12 (m, 3H), 6.37 (br s, NH), 4.30-4.26 (m, 2H), 4.07 (s, 6H), 3.60 (m, 1H), 3.18 (m, 2H), 2.30 (s, 3H), 2.17 (m, 2H), 2.01-1.98 (m, 2H); LC/MS (ESI) calcd mass 406.2, found 407.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH:14]([NH:17][C:18]([C@@H:20]1[C@H:25]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29]([NH2:34])[C:28]=2[NH2:35])[C@@H:24]2[CH2:36][C@H:21]1[CH:22]=[CH:23]2)=[O:19])([CH3:16])[CH3:15].C([O-])(=O)C.[NH4+]>>[CH:14]([NH:17][C:18]([C@@H:20]1[C@H:25]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29]3[NH:34][C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:13][CH2:12][CH2:11][CH2:10]5)=[N:3][C:2]=4[Cl:1])=[N:35][C:28]=23)[C@@H:24]2[CH2:36][C@H:21]1[CH:22]=[CH:23]2)=[O:19])([CH3:16])[CH3:15]
Reactant: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1sc(N2CCCC2)nc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 3.4 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-pyrrolidin-1-yl-thiazole-5-carbaldehyde (69.84 mg, 0.3223 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid isopropylamide (97.42 mg, 0.2901 mmol), and Ammonium acetate (44.72 mg, 0.5802 mmol) were reacted to produce 5.21 mg (3.4%) of the title compound. (300 MHz, DMSO-d6) 12.60 (s, 1H), 8.10 (d, J=8 Hz, 1H), 7.93 (s, 1H), 6.90 (s, 1H), 6.34 (m, 2H), 5.00 (t, J=17 Hz, 8.5 Hz, 1H), 3.88 (m, 1H), 3.44 (m, 4H), 2.83 (s, 1H), 2.76 (s, 1H), 2.55 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 2.01 (m, 4H), 1.37 (d, J=8 Hz, 1H), 1.07 (d, J=7 Hz, 3H), 1.00 (d, J=7 Hz, 3H). MS=531 (M+H), HPLC: 3.11 min. (G Method)
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=3[Cl:27])=[C:12]([F:28])[CH:11]=2)[C:7]([CH3:29])=[N:6][C:5]=1[CH3:30])(=[O:3])[NH2:2].[C:31](=O)([O-])[O-:32].[K+].[K+].C=O.Cl>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH2:31][OH:32])[C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=3[Cl:27])=[C:12]([F:28])[CH:11]=2)[C:7]([CH3:29])=[N:6][C:5]=1[CH3:30])(=[O:3])[NH2:2]
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(CO)c1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(Cl)c1
Temperature: 30 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
A stirred solution of methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′-fluorobiphenyl-4-yl)acetate (Intermediate 31-7; 615 g, 1437 mmol) in DMF (2.5 L) was cooled to 15° C., under a nitrogen atmosphere. Potassium carbonate (214 g, 1545 mmol) was then added followed by paraformaldehyde (47.5 g, 1581 mmol). The reaction was stirred for 5 hours at 30° C. The reaction was then added to stirred water (25.0 L) and ethyl acetate (10.0 L). Concentrated hydrochloric acid (430 ml) was then added slowly with stirring. The aqueous layer was separated and extracted with ethyl acetate (7.5 L). The organics were combined and washed with, 50% brine/water (10.0 L), dried (magnesium sulphate), filtered and the solvent was removed in vacuo. Gave methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]-3-hydroxypropanoate (762 g) as a yellow gum, 64% by LCMS (therefore 488 g, 74% yield). The material was used crude in the next stage.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:10]=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[C:5]([CH:10]=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccnc1C=O
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of 3-nitropicolinaldehyde (500 mg, 3.28 mmol) in EtOH (10 mL) was added Pd/C (50 mg) under nitrogen atmosphere. The reaction mixture was stirred for overnight under hydrogen atmosphere. The reaction mixture was filtered through cilite and washed with EtOH. The filtrate was concentrated in vacuo to give 3-aminopicolinaldehyde (200 mg, 50% yield): 1H NMR (400 MHz, DMSO-d6) δ 7.132 (br s, 2H), 7.217-7.325 (m, 2H), 7.979 (dd, J=1.6 Hz, J=4.0 Hz, 1H), 9.899 (s, 1H); LC-MS (ESI) m/z 123.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][CH2:8][C:7]1=O)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30].N1C=CC=CC=1>C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][CH2:8][C:7]1=[S:30])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)CN1C(=O)CN=C(c2ccccc2)c2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CN1C(=S)CN=C(c2ccccc2)c2cc(C(F)(F)F)ccc21

Procedure:
A mixture of 0.01 mole of 7-trifluoromethyl-2,3dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetic acid ethyl ester and 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 2,3-dihydro-5-phenyl-2-thioxo-7-(trifluoromethyl)-1H-1,4-benzodiazepin-1-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:25]([OH:27])=[O:26])=[C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:7]2[CH:16]1[CH2:18][CH2:17]1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH2:36][CH2:37][NH2:38].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O.O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:38][CH2:37][CH2:36][NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:25]([OH:27])=[O:26])=[C:6]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)c(-c3ccccc3)n(C3CC3)c12
Reactant: NCCNc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)c(-c3ccccc3)n(C3CC3)c12
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
A solution of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-2-phenylquinoline-3-carboxylic acid (550 mg, 1.42 mmol), N-2-pyridyl-1,2-ethanediamine (292 mg, 2.13 mmol) and triethylamine (0.297 mL, 2.13 mmol) in DMSO (7 mL) was stirred at 120° C. for 6 h. To the reaction mixture, water and NH4Cl was added to neutralize and the suspension was stirred for 30 min. The crude product was extracted with EtOAc, washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography (Hexane:EtOAc 1:1→1:5) to yield 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-2-phenyl-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (356 mg, 50%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[S:28][C:29]([Br:32])=[CH:30][CH:31]=1)=O>>[Br:32][C:29]1[S:28][C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(Br)s1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Br)s3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 33 %

Procedure:
4-[4-(5-Bromo-thiophen-2-yl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (180 mg, 33%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-(5-bromothiophen-2-yl)ethanone (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.50 (d, J=1.8 Hz, 1H), 8.13-8.22 (m, 3H), 7.52 (d, J=3.9 Hz, 1H), 7.40-7.48 (m, 2H), 7.28 (d, J=3.9 Hz, 1H).