Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:16][CH:13]2[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(CBr)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
5 g of 4-(bromomethyl)benzenesulfonyl chloride (18.6 mmol, 1 eq.) were dissolved under argon atmosphere in 82.5 ml of dichloromethane and cooled down at −10° C. internal temperature. A solution of 1.29 ml cyclopropanamine (18.6 mmol, 1 eq.) and 2.59 ml of triethylamine (18.6 mmol, 1 eq.) in 82.5 ml of dichloromethane were added dropwise at −10° C. internal temperature and stirred at this temperature for one hour. The reaction mixture was washed once with 1 M aqueous hydrogen solution and twice with distilled water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product contained a mixture of bromomethyl- and chloromethyl-substituents.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])O[C:4]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH2:14][C:3]1=2.[OH-].[NH4+:20]>>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[NH:20][C:4]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH2:14][C:3]1=2
Reactant: O=C(O)c1cc(=O)c2c(o1)-c1ccccc1SC2
Reactant: [NH4+]
Agent: [OH-]
Product: O=C(O)c1cc(=O)c2c([nH]1)-c1ccccc1SC2

Procedure:
A solution of 4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carboxylic acid (3.0 g, 11.53 mmoles, described in Example 79 ) in concentrated ammonium hydroxide (50 ml) is heated on a steam bath for 2.5 hr., and evaporated under reduced pressure. The residue is dissolved in water (75 ml) and added to a mixture of concentrated hydrochloric acid (5 ml) and ice. The precipitate is collected, washed with 0.07 N hydrochloric acid, acetone and ether to give the title compound as light yellow crystals, m.p. 256°-257° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[C:5]2[CH:8]=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.[N+:15]([O-])([O-:17])=[O:16].[NH4+]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2c(c1C)OC(C)(C)C2=O
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1c([N+](=O)[O-])cc2c(c1C)OC(C)(C)C2=O
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 2,2,6,7-tetramethyl-1-benzofuran-3 (2H)-one obtained in Reference Example 41 (5.20 g, 27.3 mmol) in anhydrous trifluoroacetic acid (50 mL) and chloroform (5 mL) was added ammonium nitrate (2.10 g, 32.8 mmol) at 0° C., and the mixture was stirred at the same temperature for 2 hours, and then concentrated under reduced pressure. Water was added to the residue, which was extracted with ethyl acetate. The extract was washed with water and a saturated sodium hydrogen carbonate solution, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to obtain 5.40 g (yield 84%) of the title compound. Melting point: 131-132° C. (ethyl acetate-hexane).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:43])[C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]([N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([CH:39]4[CH2:41][CH2:40]4)[CH2:31][CH2:30]3)=[O:28])=[CH:15][C:14]=2[Cl:42])=[N:8][C:7]=1[CH3:44])=[O:5])C.O.O.[OH-].[Li+]>O1CCOCC1>[Cl:42][C:14]1[CH:15]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[C:27]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH:39]3[CH2:40][CH2:41]3)[CH2:31][CH2:30]2)=[O:28])[C:17]([Cl:19])=[CH:18][C:13]=1[C:12]([NH:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:44])[N:8]=1)=[O:43]
Reactant: CCOC(=O)c1sc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)sc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
To a solution of 0.16 g (0.25 mmol) 2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-4-methyl-thiazole-5-carboxylic acid ethyl ester (Example 45) in 2 mL dioxane were added 2 mL water and 0.013 g (0.31 mmol) lithiumhydroxide monohydrate. The resulting suspension was stirred at room temperature for 2 hours and then stirred at reflux temperature for 5.5 hours. Another 0.013 g (0.31 mmol) lithiumhydroxide monohydrate were added and heating was continued for another 8 hours. The oil bath was removed and the reaction mixture was stirred at room temperature overnight. After evaporation of the organic solvent the pH of the resulting solution was adjusted to 2 to 3 using 1M aqueous hydrochloric acid and the solution was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The product was purified by preparative HPLC (Phenomenex Gemini Column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 0.058 g (37%) of the title compound as a light brown solid. MS (ESI): m/z=624.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24](CC3C=CC(OC)=CC=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2.[CH3:39][N:40](C=O)C>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.[C-]#N.[Zn+2].[C-]#N>[C:39]([C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2)#[N:40]
Reactant: CN(C)C=O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(C)C)cc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)c1ccc(N2CCOc3cc(S(=O)(=O)Nc4nccs4)ccc32)c(C#N)c1

Procedure:
A reaction vial was charged with 4-(2-bromo-4-isopropylphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.175 g, 0.285 mmol), Pd(PPh3)4 (0.049 g, 0.043 mmol), and zinc cyanide (0.050 g, 0.427 mmol), and DMF (1.139 ml) was added. The reaction was sealed and heated to 100° C. overnight until complete conversion to the desired product. The reaction was diluted with ethyl acetate and filtered over a membrane, washing with ethyl acetate. The filtrate was then washed with small amounts of water (×4) to remove residual DMF. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude yellow oil. The oil was dissolved in methanol and was loaded onto a 2-g SCX column (product eluted with methanol wash). After concentration, the crude product was diluted with DCM (2.0 mL) and TFA (1.0 mL) was added and the reaction was stirred at RT for 30 minutes until complete deprotection. The reaction was then concentrated in vacuo, and was purified by silica gel chromatography eluting with 0-100% ethyl acetate in heptanes to yield 4-(2-cyano-4-isopropylphenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.055 g, 0.125 mmol, 43.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.94 Hz, 6 H) 2.93-3.05 (m, 1 H) 3.72-3.77 (m, 2 H) 4.30-4.36 (m, 2 H) 6.42 (d, J=8.41 Hz, 1 H) 6.79 (d, J=4.60 Hz, 1 H) 7.13-7.17 (m, 1 H) 7.18 (d, J=2.15 Hz, 1 H) 7.22 (d, J=4.60 Hz, 1 H) 7.49 (d, J=8.41 Hz, 1 H) 7.68 (dd, J=8.46, 2.20 Hz, 1 H) 7.83 (d, J=2.15 Hz, 1 H) 12.58 (br. s., 1 H). m/z (ESI) 441.3 (M+H)+.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]3[CH2:30][O:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[N:14][C:13]=2[CH:38]=1>CO>[ClH:1].[CH3:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH:18]3[CH2:30][O:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[N:14][C:13]=2[CH:38]=1
Reactant: Cc1ccc2oc(N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)nc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc2oc(N3CCNCC3COc3cccnc3)nc2c1
Reaction time: 8 h
Yield: 34 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(5-methylbenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (212.9 mg, 0.502 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1 equiv. HCl, 0.057 mL) was added. The mixture was concentrated under reduced pressure to give 60.8 mg (34%) of the desired product as the hydrochloride salt. LC-MS: RT=4.45 min, [M+H]+=325.1.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[SH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>ClCCl>[C:22]([CH2:21][CH2:20][S:19][CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)([OH:24])=[O:23]
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Reactant: O=C(O)CCS
Solvent: ClCCl
Product: O=C(O)CCSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.7 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (305 mg) was dissolved in dichloromethane (10 ml) and 3-mercaptopropionic acid (0.09 ml) was added. The solution was stirred at room temperature for 3 days, during which time a yellow precipitate was formed. This precipitate was filtered off and recrystallised from absolute ethanol to give 10-(carboxyethylthio)-1,8-dihydroxy-9-anthrone (240 mg, 72.7%) as pale yellow needles, melting point 152°-153° C. (Found: C 61.5, H 4.3, S 9.8%; M=330.0548; C17H14O5S requires C 61.8, H 4.3, S 9.7%; M=330.0562).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([NH:12]C(OCC3C=CC=CC=3)=O)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([NH2:12])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1(c2cccc(F)c2)CCC1)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NC1(c2cccc(F)c2)CCC1
Temperature: 15 °C
Reaction time: 0.75 h
Yield: 82.7 %

Procedure:
A stirred solution of 1-(3-fluorophenyl)cyclobutanecarbamic acid, benzyl ester (8.25 g, 27.6 mmol) and ammonium formate (5.04 g, 79.9 mmol) in methanol (120 mL) under N2 is cooled to 15° C. Ten percent palladium on carbon (1.5 g) is added portionwise over 10 minutes. The reaction mixture is stirred at 15° C. for 45 minutes, then filtered through a small pad of celite. The filter cake is washed with methanol. The filtrate is concentrated. The resulting white solid is partitioned between dichloromethane (150 mL) and saturated aqueous bicarbonate (150 mL). The phases are separated and the aqueous phase extracted with dichloromethane (3×75 mL). The combined organics are washed with saturated aqueous bicarbonate (1×100 mL), water (1×100 mL) and brine (1×100 mL), dried (MgSO4), filtered and concentrated. The organic residue is purified by flash chromatography using 2.5% methanol (saturated with ammonia) in dichloromethane as the eluent to afford 3.77 g of 1-(3-fluorophenyl)cyclobutanamine. This product is the amine used in Step B-2. 1H NMR (CDCl3) δ7.32 (m, 1 H), 7.19 (m, 1 H), 7.09 (m, 1 H), 6.94 (m, 1 H), 2.54 (m, 2 H), 2.12 (m, 3 H), 1.80 (m, 1 H), 1.70 (s, 2 H); 13C NMR (CDCl3) δ164.6, 161.3, 151.99, 151.90, 129.9, 129.8, 120.54, 120.50, 113.3, 113.0, 112.2, 111.9, 58.8, 36.9, 14.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[C:4]([CH3:13])[CH:3]=1.C(N(CC)CC)C.Cl[C:22]1[N:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:23]=1[C:24]([NH:26][C:27]1([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:25]>O1CCCC1.CO>[Cl:44][C:41]1[CH:42]=[N:43][C:22]([N:11]2[CH2:12][CH:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:13])[CH2:10]2)=[C:23]([CH:40]=1)[C:24]([NH:26][C:27]1([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[CH2:29][CH2:28]1)=[O:25]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Reactant: Cc1cc(F)ccc1NC1CNC1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4C)C3)CC2)cc1
Temperature: 75 °C

Procedure:
To a solution of N-(4-fluoro-2-methylphenyl)azetidin-3-amine (D55) and triethylamine (0.14 ml, 1.04 mmol) in tetrahydrofuran/methanol (3 ml/1 ml) methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D97) (253 mg, 0.693 mmol) was added and the resulting mixture was heated 24 h at 75° C. The residue obtained after solvent evaporation, was purified by Biotage SNAP-Si (10 g) cartridge eluting with eluting with a mixture dichloromethane/ethylacetate from 95/5 to 80/20. Collected fractions, after solvent evaporation afforded the title compound (D168) (105 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-])=O)=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:15].[Cl-].[NH4+].C(Cl)Cl>CCO.O.[Fe]>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:15]
Reactant: CN1C(=O)COc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CN1C(=O)COc2cc(N)ccc21
Temperature: 80 °C

Procedure:
To a stirred suspension of 4-methyl-7-nitro-2H-1,4-benzoxazin-3-one (DE 19802239, 2.43 g, 11.67 mmol) in EtOH (20 mL) and water (10 mL) is added ammonium chloride (6.25 g, 116.70 mmol). To this mixture is added iron (1.95 g, 35.00 mmol) in 3 equal portions. The resulting mixture is heated to 80° C. for 2 h at which time the reaction is cooled to room temperature followed by addition of CH2Cl2 (100 mL). The resulting mixture is filtered through celite and the filtrate is further diluted with water (100 mL). The organic layer is separated followed by further extraction of the aqueous phase with CH2Cl2 (3×50 mL). The organic phases are combined, dried over Na2SO4 and concentrated under reduced pressure, and the product is purified by silica gel column chromatography (EtOAc) to give the title compound in quantitative yield, MS m/z 179.1 (M+H)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O[C:14]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([C:21]1[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=1)=[CH2:20]
Reactant: CC(C)(C)CC(C)(O)c1ccc(C#N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(CC(C)(C)C)c1ccc(C#N)cc1
Temperature: 100 °C
Yield: 61.9 %

Procedure:
Add p-toluenesulfonic acid monohydrate (308 mg, 1-62 mmol) to a solution of 4-(1-hydroxy-1,3,3-trimethyl-butyl)-benzonitrile (352 mg, 1.62 mmol) in toluene (10 mL). Heat the solution to 100° C. for 30 min. Cool the reaction mixture to room temperature, dilute the reaction mixture with EtOAc and wash the organic phase with saturated aqueous NaHCO3. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (98:2, 19:1) to give the desired intermediate as an oil (200 mg, 62%).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:12]=[C:11](OC2C=CC=CC=2)[C:10]2[N:20]=[CH:21][N:22]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]=2[C:8]=1[CH3:32]>ClCCl>[CH3:6][C:7]1[N:12]=[C:11]([NH2:5])[C:10]2[N:20]=[CH:21][N:22]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]=2[C:8]=1[CH3:32]
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2ncn(CCOc3ccccc3)c2c1C
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Cc1nc(N)c2ncn(CCOc3ccccc3)c2c1C
Temperature: 150 °C

Procedure:
A sealed tube containing ammonium acetate (12.7 g) and 6,7-dimethyl-4-phenoxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridine (1.27 g) from Part E was heated to 150° C. for 36 hours. HPLC and TLC analysis indicated that the reaction was complete. The reaction was allowed to cool to room temperature. The resulting reaction mixture was then dissolved in dichloromethane (DCM) and washed with 20% aqueous sodium hydroxide. The basic layer was washed with DCM and the combined organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting oil was passed through a silica gel column using 95/5 dichloromethane/methanol as the eluant. The product was recrystallized from isopropyl alcohol, and the resulting white solid was dried under vacuum to provide 6,7-dimethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 197.0–199.0° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(Cl)(Cl)[Cl:23].S(Cl)(Cl)=O>CN(C)C=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([Cl:23])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 1 h

Procedure:
1.0 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 25 ml. of chloroform, and 1 ml. of thionyl chloride and 0.1 ml. of dimethylformamide are added thereto. The mixture is left for 1 hour then evaporated under high vacuum to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride. In similar manner, substituting the acids prepared in Preparations 3 and 5-9 for the 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid used above, the corresponding acid chlorides are prepared.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH4-].[Na+]>CO>[C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Yield: 96.9 %

Procedure:
To a stirring solution of p-BocNHCH2C6H4NO2 (7.5 g, 29.7 mmol) and NiCl2.6H2O (17.7 g, 74.3 mmol) in methanol (150 mL) at 0° C. was added NaBH4 (5.6 g, 149 mmol) in small portions over 30 min. After complete addition of NaBH4 and 15 min, the solvent was evaporated in vacuo and the residue was dissolved in conc. ammonium hydroxide and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 6.4 g (97%) of a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1>C(#N)C>[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:22]1
Reactant: NCC1CCCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCC(CN)C3)nc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.9 %

Procedure:
A mixture of 1.04 g (3.84 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 100 ml of acetonitrile and 1.32 g (11.5 mmole) of 3-aminomethylpiperidine [J. Org. Chem., 44, 4536 (1979)] were stirred at room temperature for four days. The reaction was filtered and the precipitate dissolved in aqueous ammonia, pH 10.5. The solution was filtered and the solvent removed at reduced pressure. The product was washed with water, then ether until dry to give 1.23 g of 7-[3-(aminomethyl)-1-piperidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 120°-122° C.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH2:58][CH2:57][N:56]([C:59]3[N:60]=[C:61]([N:69]4[CH2:73][CH2:72][CH2:71][C@H:70]4[CH2:74][NH2:75])[C:62]4[S:67](=[O:68])[CH2:66][CH2:65][C:63]=4[N:64]=3)[CH2:55][CH2:54]2)=[CH:49][CH:48]=1>CS(C)=O.ClCCl.O>[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH2:54][CH2:55][N:56]([C:59]3[N:60]=[C:61]([N:69]4[CH2:73][CH2:72][CH2:71][C@H:70]4[CH2:74][NH:75][C:1](=[O:5])[CH2:2][CH3:3])[C:62]4[S:67](=[O:68])[CH2:66][CH2:65][C:63]=4[N:64]=3)[CH2:57][CH2:58]2)=[CH:49][CH:48]=1
Reactant: NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Reactant: CCC(=O)O
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: O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
17 μl propionic acid are placed in 800 μl dimethylsulphoxide, and 78 μl diisopropylethylamine and 94 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. The mixture is stirred for 0.3 hours at ambient temperature, then a solution of 100 mg C—((S)-1-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-pyrrolidin-2-yl)-methylamine trifluoroacetate, Diastereomer 2 (Example 226) (see scheme 3, 3.17.2), in 700 μl dimethylsulphoxide is added. The reaction mixture is stirred for 15 hours at ambient temperature and then combined with water and dichloromethane. The organic phase is dried and evaporated to dryness. The product is purified by preparative HPLC (method A). 84 mg of the product are obtained as an oil. Analytical HPLC-MS (method D): RT=1.19 min.
Reaction SMILES: C(OC1C(F)=CC=C2C=1C(CCN(C)C)=CN2)C1C=CC=CC=1.[F:24][C:25]1[CH:26]=[C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:28]([O:41][CH3:42])=[C:29]2[C:33]=1[N:32]([CH3:34])[CH:31]=[C:30]2[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=O>>[F:24][C:25]1[CH:26]=[C:27]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:28]([O:41][CH3:42])=[C:29]2[C:33]=1[N:32]([CH3:34])[CH:31]=[C:30]2[CH2:35][CH2:36][N:38]([CH3:39])[CH3:40]
Reactant: COc1c(-c2ccccc2)cc(F)c2c1c(CC(=O)N(C)C)cn2C
Agent: CN(C)CCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Product: COc1c(-c2ccccc2)cc(F)c2c1c(CCN(C)C)cn2C

Procedure:
Following the procedure used to prepare compound 1-7a (step 6 scheme 1), compound 8-12 gave compound 8-13
Reaction SMILES: [BH4-].[Na+].[CH:3](=[N:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:4]>CO>[CH2:3]([NH:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:4]
Reactant: CC=NC1CCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNC1CCCCCC1
Temperature: 10 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Sodium borohydride (3.78 g) was gradually added with ice bath cooling to a methanol (600 ml) solution of N-ethylidenecycloheptylamine (41.7 g) and agitated at 10° C. for 3 hours. Thereafter, the solvent was distilled off, followed by extraction with methylene chloride. Then, the extract was dried over anhydrous magnesium sulfate. Methylene chloride was distilled off and the obtained oil was distilled under reduced pressure to obtain N-ethylcycloheptylamine (35.96 g). b.p. 110°-113° C./26.6 mbar.