Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(COC([NH:11][CH:12]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][CH2:30][CH2:31][NH:32][C:33]2[N:34]([C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:35]=[CH:36][N:37]=2)[N:24]=[CH:23]3)=[O:19])[C:13]([OH:15])=[O:14])=O)C=CC=CC=1>C(O)C.[Pd]>[NH2:11][CH:12]([CH2:16][NH:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:29][CH2:30][CH2:31][NH:32][C:33]1[N:34]([C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:35]=[CH:36][N:37]=1)[N:24]=[CH:23]2)=[O:19])[C:13]([OH:15])=[O:14]
Reactant: O=C(NC(CNC(=O)c1ccc2c(cnn2CCCNc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1)C(=O)O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC(CNC(=O)c1ccc2c(cnn2CCCNc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1)C(=O)O
Yield: 35.1 %

Procedure:
2-((Phenylmethoxy)carbonylamino-3-((1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.750 g, 1.00 mmol) was added to Pd/C (1.00 g) in ethanol (20 mL). The reaction was evacuated and purged with nitrogen twice. The reaction was then evacuated and purged with hydrogen twice, and then maintained under an atmosphere of hydrogen for 24 h. The reaction was filtered through celite. The filtrate was concentrated to an oil. The oil was recrystallized from hexane:ethyl acetate to give 215.6 mgs (35%) of product. ESMS: Calcd. for C36H35N7O3, 613.28. Found, 614.2 [M+H]+1 Analytical HPLC, Method A, Rt=12.26 min, Purity=90%.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.Br[CH2:31][C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[CH2:31][N:19]1[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20]1(=[O:27])=[O:28]
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Reactant: BrCc1nc2ccccc2s1
Product: Cc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1Cc1nc3ccccc3s1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 2-bromomethyl-benzothiazole. MS: ESI (negative): 502 (M−H).
Reaction SMILES: [IH:1].[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]=[C:13](SC)[NH2:14])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:17](N)[CH2:18][NH2:19]>CO>[IH:1].[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]=[C:13]2[NH:14][CH2:17][CH2:18][NH:19]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CSC(N)=NC(=O)Nc1cccc(Cl)c1
Reactant: NCCN
Agent: I
Solvent: CO
Product: O=C(N=C1NCCN1)Nc1cccc(Cl)c1

Procedure:
To 37.1 grams (0.1 mole) of methyl N'-{[(3-chlorophenyl)amino]carbonyl}-carbamimidothioate hydroiodide thus prepared is added 6.0 grams (0.1 mole) of ethylenediamine in 100 milliliters of methanol and the resulting mixture allowed to heat under reflux for five hours. The resulting reaction mixture is evaporated to dryness in vacuo and diluted with tertiary-butyl alcohol to obtain crystals of N-(3-chlorophenyl)-N'-(2-imidazolidinylidene) urea hydroiodide product as a crystalline solid. The crystals are recrystallized from tertiary butyl alcohol several times to obtain a purified product, m.p. 192°-194° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38](C(OC(C)(C)C)=O)[CH:39]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:35]3[CH:36]=[N:37][NH:38][CH:39]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
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: COCCOC
Product: O=C(Nc1ccnnc1)c1cc(-c2cn[nH]c2)ccc1OCc1ccc(F)c(F)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}-N-4-pyridazinylbenzamide (may be prepared as described in Example 78; 150 mg, 0.36 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (116 mg, 0.39 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.71 ml, 0.71 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.75 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 25 min under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated under reduced pressure and the residue was purified using the MDAP to yield the title compound. 41 mg.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:16][C:15]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cn3c(n2)CCCC3)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1c(-c2ccccc2)nc2n1CCCC2
Yield: 82 %

Procedure:
To a solution of 2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine (1.7 g, 8.9 mmol) in dry CH2Cl2 (55 mL) slowly add bromine (0.5 mL, 9.8 mmol) and stir at room temperature for 3 hours. Then, add a saturated aqueous solution of NaHCO3 (100 mL) and extract with CH2Cl2 (3×100 mL). Wash the combined organic layers with NaHSO3 (40%, 30 mL) followed by saturated aqueous sodium chloride (50 mL), dry (MgSO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, eluent:CH2Cl2 to CH2Cl2/MeOH 20:1) to obtain a brown solid, 2.0 g, 82% yield. MS((ES+): m/z=277.0, (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.Cl.C([O:21][C:22](=[O:31])[C@@H:23]([NH2:30])[CH2:24][O:25]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:30][C@@H:23]([CH2:24][OH:25])[C:22]([OH:31])=[O:21])=[O:15])[N:3]=1
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: O=C(N[C@@H](CO)C(=O)O)c1nc(Cl)c2ccccc2c1O

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid from Example A-2 d) and (S)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=310.9 amu.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].O1CCCC1>O>[C:26]([O:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][C:4]=1[C:1]([OH:3])=[O:2])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)ccc1O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1C(=O)O

Procedure:
A mixture of 25.0 g. (0.075 mole) of 1-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole and 225 g. (2.25 mole) of acetic anhydride was heated under reflux for 3 hours, diluted with 200 ml. of tetrahydrofuran, and poured into 3 l. of water. An oil separated and slowly solidified. Recrystallization from acetic acid gave a tan solid, m.p. 155°-162°.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([OH:20])=O)[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([NH2:31])[CH3:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([NH:31][CH2:29][CH3:30])=[O:20])[C:14]1([CH3:22])[CH3:23])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCN
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)NCC)C1(C)C

Procedure:
The product from Example 205 and ethylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 0.98 (t, J=7.7 Hz, 3H), 1.13 (s, 3H), 1.23 (s, 3H), 1.26-1.40 (m, 3H), 1.57 (s, 9H), 1.57-1.66 (m, 2H), 1.71-1.82 (m, 1H), 2.24-2.47 (m, 2H), 2.61-2.67 (m, 2H), 2.96-3.11 (m, 3H), 7.28-7.31 (m, 1H), 8.50 (s, 1H). (ESI+) m/z 422 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:8](C(O)=O)=[CH:9][C:5]=2[S:4][CH:3]=1.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Br:1][C:2]1[C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[CH:8]=[CH:9][C:5]=2[S:4][CH:3]=1
Reactant: O=C(O)c1cc2scc(Br)c2n1Cc1ccc(C(F)(F)F)cc1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)c1ccc(Cn2ccc3scc(Br)c32)cc1
Temperature: 140 °C
Yield: 82.3 %

Procedure:
A mixture of 3 g of the product of Step 4 and 0.3 g of copper powder in 50 ml of quinoline was heated in oil bath at 140° C. for 4 h. The reaction mixture was cooled and acidified with 6 N HCl and then extracted with 150 ml of ether. The ether layer was washed with 200 ml of 2 N HCl, dried over Na2SO4, filtered, and concentrated to give 2.2 g of the title compound as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[NH2:22])[CH:5]=[CH:6][CH:7]=1.[CH3:23]OC(OC)OC>C(Cl)Cl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]3[N:8]([C:4]4[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=4)[CH:23]=[N:22][C:10]=3[CH:11]=2)=[CH:16][CH:17]=1
Reactant: COC(OC)OC
Reactant: Nc1cccc(Nc2ccc(-c3ccc(F)cc3)cc2N)c1
Solvent: ClCCl
Product: Nc1cccc(-n2cnc3cc(-c4ccc(F)cc4)ccc32)c1
Temperature: 120 °C

Procedure:
A solution of N*4*-(3-Amino-phenyl)-4′-fluoro-biphenyl-3,4-diamine (Procedure O3, ˜5.1 mmol) in trimethylorthoformate (30 ml) was stirred and heated at 120° C. under N2 for 10 hours. The volatiles were removed in vacuo and the residue was taken up in EtOH (30 ml) and treated with c.HCl (2 ml), then stirred and heated at reflux for 3 hours. After cooling to RT, the mixture was concentrated to ˜2 ml, then diluted with H2O. NaHCO3 (sat) was added to give ˜pH7.5. The solid was taken up in CH2Cl2. The organic layer was dried and evaporated. The residue was purified by chromatography on silica (0%→1%→>2% 2M NH3-MeOH/CH2Cl2). The material was then triturated with Et2O to give the title compound (890 mg) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:21](C)=O.[Na+].C([O-])(O)=O.[Na+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:21])[CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The crude piperazine-1,3-dicarboxylic acid-1-tert-butyl ester (4.92 mmol), prepared as described in 62(A), was suspended in dry acetonitrile (30 mL) under nitrogen atmosphere and formaldehyde (37% wt. aqueous solution, 367 mL, 4.92 mmol) and Na(OAc)3BH (2.3 g, 10.82 mmol) were added. The resulting mixture was stirred at R.T. for 3 h, then a saturated aqueous solution of NaHCO3 was slowly added until the pH was adjusted to 7. The mixture was concentrated to dryness under reduced pressure to give a yellow solid that was used without further purification for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][Si](C)(C)C)=[CH2:5])[CH3:2].[CH3:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][O:18][CH2:19][CH:20]([CH2:23][CH:24]=[CH2:25])[CH:21]=[O:22])=[CH:15][CH:14]=1>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[OH:22][CH:21]([CH:20]([CH2:19][O:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:27][CH:26]=1)[CH2:23][CH:24]=[CH2:25])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: C=CCC(C=O)COCc1ccc(OC)cc1
Reactant: C=C(OCC)O[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC(COCc1ccc(OC)cc1)C(O)CC(=O)OCC
Temperature: -78 °C

Procedure:
A methylene chloride solution (10 mL) of titanium tetrachloride (0.97 mL, 8.88 mmol) and [(1-ethoxyvinyl)oxy](trimethyl)silane (J. Am. Chem. Soc. 2003, 125, 5644) was added to a methylene chloride solution (80 mL) of 2-{[(4-methoxybenzyl)oxy]methyl}pent-4-enal (Tetrahedron: Asymmetry 2001, 12, 3223) (1.98 g, 8.46 mmol) with stirring at −78° C., and the mixture was stirred at this temperature for 1.5 hours. The reaction was terminated by the addition of a saturated aqueous solution of sodium bicarbonate (100 mL) and water (100 mL), followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (1.31 g, 48%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[C:3]=1[O:32][CH2:33][CH3:34].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:11]2[C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[C:3]=1[O:32][CH2:33][CH3:34]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(/C(CC)=C(F)\C=C\C(C)=C\C(=O)O)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure J-1, ethyl (2E,4E,6E)-7-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6-fluoro-3-methyl-nona-2,4,6-trienoate (Compound A-159, 930 mg, 1.74 mmol) in ethanol was treated with a solution of 1 N NaOH to produce the title compound after purification by recrystallization from acetonitrile.
Reaction SMILES: [ClH:1].[CH3:2][O:3][CH2:4][C@H:5]1[N:15]2[C@@H:9]([S:10][CH2:11][CH2:12][C@H:13]([NH:17]C(=O)OC(C)(C)C)[C:14]2=[O:16])[CH2:8][CH2:7][CH2:6]1>>[ClH:1].[NH2:17][C@H:13]1[CH2:12][CH2:11][S:10][C@H:9]2[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:4][O:3][CH3:2])[N:15]2[C:14]1=[O:16]
Reactant: COC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Agent: Cl
Product: COC[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of HCl (4.0 N in dioxane, 1 mL) was added to a reaction flask containing tert-butyl (4S,7S,10aS)-7-(methoxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (83 mg, 0.24 mmol). The reaction mixture was then stirred at rt overnight. The reaction mixture was concentrated. Ether was added to the residue. A white solid formed. The mixture was stirred for 5 min and then filtered. The solid was dried under vacuum to give (4S,7S,10aS)-4-Amino-7-(methoxymethyl)hexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one hydrochloride (63 mg, 0.22 mmol, 93% yield) as a white solid. Anal. Calcd. for C11H20N2O2S m/z 244.4. found: 245.1 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(C)(C)C.Br[CH2:19][CH2:20][CH2:21][CH2:22]Br>>[N+:14]([C:10]1[CH:9]=[C:8]([C:7]2([C:6]([OH:5])=[O:17])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)Cc1cccc([N+](=O)[O-])c1
Product: O=C(O)C1(c2cccc([N+](=O)[O-])c2)CCCC1

Procedure:
Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,4-dibromobutane (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 1-(3-nitrophenyl)cyclopentanecarboxylic acid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH2:39][CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: CN1CCC(CN)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCN(C)CC3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1-methlpiperidin-4-yl)methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-1.29 (m, 1H) 1.32-1.46 (m, 2 H) 1.80 (d, J=3.54 Hz, 1 H) 1.91 (d, J=13.64 Hz, 2 H) 2.44 (s, 3 H) 2.71-2.84 (m, 3 H) 2.85-3.00 (m, 2 H) 3.23 (t, J=6.19 Hz, 2 H) 3.45 (br. s., 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.71-7.90 (m, 2 H) 8.22 (d, J=13.64 Hz, 1 H) 8.43 (br. s., 2 H) 8.82 (br. s., 1 H) 8.93 (dd, J=2.02, 0.76 Hz, 1 H) 9.28 (br. s., 1 H) 13.23 (br. s., 1 H). MS m/z [M+H]+ 431.2.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:19]([F:36])=[CH:20][C:21]4[C:31](=[O:32])[C:30]([C:33]([OH:35])=[O:34])=[CH:29][N:23]5[CH:24]([CH3:28])[CH2:25][O:26][C:27]=3[C:22]=45)[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.[ClH:37]>>[ClH:37].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:19]([F:36])=[CH:20][C:21]4[C:31](=[O:32])[C:30]([C:33]([OH:35])=[O:34])=[CH:29][N:23]5[CH:24]([CH3:28])[CH2:25][O:26][C:27]=3[C:22]=45)[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CC1COc2c(N3CC4CCOC4(CNC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Product: CC1COc2c(N3CC4CCOC4(CN)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 10-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid hydrochloride with a melting point of 220°-227° C. (with decomposition).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][NH:12][CH:13]([CH:17]1[CH2:19][CH2:18]1)[CH:14]1[CH2:16][CH2:15]1)CC1C=CC=CC=1>C(O)C.[Pd]>[CH3:1][NH:2][CH2:10][CH2:11][NH:12][CH:13]([CH:17]1[CH2:19][CH2:18]1)[CH:14]1[CH2:15][CH2:16]1
Reactant: CN(CCNC(C1CC1)C1CC1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNCCNC(C1CC1)C1CC1
Temperature: 45 °C

Procedure:
5.8 g of the compound obtained in Step b, in 30 ml of absolute ethanol, and 100 mg of 10% palladium-on-carbon are stirred and heated at 45° C. under a hydrogen atmosphere for 3 hours. The solvent is evaporated off. After customary treatment of the organic phase, the desired crude product is purified by distillation.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:12][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[F:13])=[N:3]2
Reactant: OB(O)c1ccccc1F
Reactant: Clc1ccc2c(Cl)ccnc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccccc1-c1ccc2c(Cl)ccnc2n1
Temperature: 80 °C
Yield: 91.6 %

Procedure:
A stirred mixture of 2,5-dichloro-[1,8]naphthyridine (Barlin, G. B.; Tan, W.-L. Aust. J. Chem. 1984, 37, 1065) (0.1029 g, 0.513 mmol) and 2-fluorobenzeneboronic acid (72.4 mg, 0.517 mmol) in 2 N aqueous sodium carbonate (0.620 mL, 1.24 mmol) and ethylene glycol dimethyl ether (3 mL) was degassed by bubbling nitrogen through for 15 min. Tetrakis-(triphenylphosphine)palladium(0) (29.9 mg, 0.0259 mmol) was added and the mixture was degassed for a further 10 min, then heated at 80° C. for 16 h under nitrogen. The mixture was partitioned between water (20 mL) and dichloromethane (20 mL). The aqueous layer was further extracted with dichloromethane (2×20 mL), and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 15% EtOAc/CH2Cl2, to afford 0.1216 g (91%) of the title compound as an off-white solid. δH (360 MHz, CDCl3) 7.22 (1H, dd, J 11.8 and 8.2), 7.34 (1H, td, J 7.7, 0.7), 7.49 (1H, tdd, J 7.4, 5.3, and 2.1), 7.58 (1H, d, J 4.7), 8.18 (1H, dd, J 8.8, 2.5), 8.39 (1H, td, J 7.7, 1.8), 8.66 (1H, d, J 8.8), 9.03 (1H, d, J 4.8).
Reaction SMILES: [S].Cl[C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[N+:13]([O-])=O.[C:16](=[S:18])=[S:17].COS(OC)(=O)=O>O>[C:8]([NH:7][C:6]1[CH:11]=[CH:12][C:3]2[S:17][C:16]([SH:18])=[N:13][C:4]=2[CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: S=C=S
Agent: [S]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CC(=O)Nc1ccc2sc(S)nc2c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
A mixture of Na2S.9H2O (65 g, 0.28 mol), sulfur (25 g, 0.78 mol) and water (150 mL) were heated with stirring at 90° C. for 10 min, and then poured into a flask charged with the above 4′-chloro-3′-nitroacetanilide (21.5 g, 0.10 mol). The resulting mixture was heated at 80° C. for 10 min, and then CS2 (12 mL, 0.2 mol) was added dropwise while maintaining a gentle reflux. The resulting mixture was heated at 90° C. for 7 h. The solids were collected by filtration, washed with water and dilute HCl solution. The solids were taken up in water, and the solution was made alkaline with solid NaOH. The solution was filtered, and the filtrate was acidified with conc HCl. The precipitates were collected by filtration, washed with water, and dried under high vacuum. The crude product was suspended in cold water (200 mL) and solid Na2CO3 was added to obtain pH 13. Dimethylsulfate was added to the above milky solution, and the resulting mixture was stirred at ambient temperature for 3 h. The solids were collected by filtration, washed with water, and dried under high vacuum to yield the title compound (12.4 g, 55%).