Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[CH:40]12[N:46]([C:47](=O)[CH2:48]Br)[CH:43]([CH2:44][CH2:45]1)[CH2:42][CH2:41]2>>[CH:40]12[N:46]([CH2:47][CH2:48][O:10][C:8]3[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]4[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=4[C@@H:14]4[CH2:23][CH2:22][C:21]5[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=5[CH2:15]4)=[CH:35][CH:34]=3)[CH:43]([CH2:44][CH2:45]1)[CH2:42][CH2:41]2
Reactant: O=C(CBr)N1C2CCC1CC2
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCCN3C4CCC3CC4)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 99.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.3 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:17]=[N:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])[CH2:22][CH2:23]3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use 4-fluorophenylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (32.3% yield). 1H NMR (500 MHz, CDCl3) δ 12.0, 8.20, 7.53, 7.64, 7.59, 7.39, 7.33, 7.16, 6.91-6.98, 3.96-4.04, 3.83-3.90, 3.52-3.65, 3.37-3.45, 3.20-3.26. MS (ES+) m/z 489 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:9])[CH:7]=[CH2:8])=[CH:2]1.[Cl:10]CCl>C(OCC)C.Cl>[Cl:10][CH2:8][CH2:7][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:9]
Reactant: C=CC(=O)c1ccsc1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: O=C(CCCl)c1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
The product from step (b) (1.288 g, 9.3 mmol) was dissolved in a mixture of diethyl ether (30 ml) and dichloromethane (20 ml) and 1M hydrochloric acid in diethyl ether (25 ml) added. The reaction was stirred for 18 h at room temperature. The solvent was removed in vacuo to give the title compound (1.482 g, 91%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[N:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=12.[F:24][C:25]1([F:43])[CH2:30][CH2:29][N:28]([C:31](OC2C=CC([N+]([O-])=O)=CC=2)=[O:32])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>>[F:24][C:25]1([F:43])[CH2:30][CH2:29][N:28]([C:31]([N:6]2[CH2:5][CH2:4][N:3]([C:8]3[N:9]=[N:10][C:11]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:12]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=34)[C@H:2]([CH3:1])[CH2:7]2)=[O:32])[CH2:27][CH2:26]1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccncc12
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(F)(F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@@H]1CN(C(=O)N2CCC(F)(F)CC2)CCN1c1nnc(-c2ccccc2)c2ccncc12
Temperature: 80 °C

Procedure:
To a 10 mL round bottomed flask was added (R)-4-(2-methylpiperazin-1-yl)-1-phenylpyrido[3,4-d]pyridazine 16 (110 mg, 360 μmol), 4-nitrophenyl 4,4-difluoropiperidin-1-carboxylate (124 mg, 432 μmol), and potassium carbonate (100 mg, 720 μmol). The reaction was heated to 80° C. overnight. After cooling to room temperature, the solvent was removed under vacuum, and the residue was redissolved in ethyl acetate and washed with water (10 mL), followed by NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (R)-(4,4-difluoropiperidin-1-yl)(3-methyl-4-(1-phenylpyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone 42. MS 452.2 (calc'd) 453.3 (M+H, found).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])O)[CH2:8][CH2:9][C:10]=2[N:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: COc1ccc(C(O)CCN2CCc3nc(N)sc3CC2)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=CCN2CCc3nc(N)sc3CC2)c(OC)c1
Reaction time: 1 h

Procedure:
0.45 g (1.2 mmol) of 2-amino-6-(3-(2,4-dimethoxy-phenyl)-3-hydroxy-1-propyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine are stirred in 35 ml of anhydrous toluene together with 0.47 g (2.7 mmol) of p-toluenesulphonic acid hydrate and 7 g of molecular sieve (4Å) in a bath at 40° C. After one hour, a further 5 g of molecular sieve are added and after a total of 2 hours a further 2.5 g of molecular sieve are added. After a total of 3 hours at 40° C. the mixture is filtered through a glass frit coated with Celite and the filter cake is washed out several times with chloroform. The toluene and chloroform solutions are extracted with semi-concentrated ammonia and with water, then dried and filtered and evaporated down in vacuo. The combined evaporation residues are purified by column chromatography on silica gel (toluene/ethyl acetate/methanol/conc. ammonia=4:3:1:0.5). Yield: 43 mg (10% of theory), Melting point: 95°-100° C. (ether).
Reaction SMILES: [ClH:1].Cl.C([S:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:9]/[C:8]/1=[CH:26]\[C:27]1[N:31]([CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:30]=[N:29][CH:28]=1)(=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[ClH:1].[CH:16]1([C:14](=[O:15])[CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([SH:6])/[C:8](=[CH:26]/[C:27]3[N:31]([CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:30]=[N:29][CH:28]=3)/[CH2:9]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:17][CH2:18]1
Reactant: CCOC(=O)CCCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Yield: 54 %

Procedure:
Hydrogen chloride was passed through a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-5-yl}methylidene)piperidine hydrochloride (4.15 g) in ethanol (50 ml) with stirring under ice-cooling for one hour and the resulting mixture was stirred at room temperature overnight under a tightly sealed condition. After concentration of the reaction mixture under reduced pressure, ethyl acetate and an aqueous sodium hydrogencarbonate solution were added to the residue. The organic layer was collected, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel chromatography using hexane and ethyl acetate (1:3) as the eluent, and the crude fraction thus obtained was further purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N aqueous hydrochloric acid solution, 40:60, v/v). The fraction obtained was neutralized with an aqueous sodium hydrogencarbonate solution. The resulting free base was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to afford the free base of the title compound (1.93 g, yield: 54%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH:8]=[C:7]2[OH:17].C(C1N=C(C2C=C(O[CH:39]3[CH2:57][CH:56]4[N:41]([C:42](=[O:62])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH:50][CH:51]5[C:53]([C:59]([OH:61])=[O:60])([NH:54][C:55]4=[O:58])[CH2:52]5)[CH2:40]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH:8]=[C:7]2[O:17][CH:39]1[CH2:57][CH:56]2[N:41]([C:42](=[O:62])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH:50][CH:51]3[C:53]([C:59]([OH:61])=[O:60])([NH:54][C:55]2=[O:58])[CH2:52]3)[CH2:40]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(O)cc(-c3nccs3)nc2c1Br
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1Br

Procedure:
The title compound was prepared from 8-bromo-4-hydroxy-7-methoxy-2-(thiazol-2-yl)quinoline (40) and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=670 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH:20]1([CH2:23][S:24][CH:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1>COCCOC.C(OCC)(=O)C>[CH:20]1([CH2:23][S:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:17]#[N:18])[CH2:27][CH2:26]2)[CH2:22][CH2:21]1
Reactant: O=C1CCC(SCC2CC2)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#CC1CCC(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
Potassium-t-butoxide (16.10 g, 144 mmol) was added to a stirred, cooled (0° C.) mixture of TOSMIC (15.84 g, 81 mmol) and 4-[(cyclopropylmethyl)thio]cyclohexanone (11.5 g, 62.4 mmol) in DME (125 ml) and the mixture was stirred at room temperature for 3 h. The mixture was cooled, diluted with ethyl acetate, washed with brine, dried, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a Biotage 65i cartridge, eluting with EtOAc/isohexane to give two separated isomers. Combined yield of 4-[(cyclopropylmethyl)thio]cyclohexanecarbonitrile (7.1 g, 36.3 mmol, 58.3% yield)
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([NH:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:3].Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3([NH:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11]3)=[CH:6][CH:5]=2)[CH3:3])[CH2:27][CH2:26]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(=O)NC1(c2ccc(C(C)Cl)cc2)CC1
Agent: Cl
Product: CC(=O)NC1(c2ccc(C(C)N3CCN(c4ncccn4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-(1-chloroethyl)phenyl)cyclopropyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyrimidyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=124-125° C.
Reaction SMILES: [C:1]([O:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[C:7](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]1=[O:27])(=[O:3])[CH3:2].[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>>[C:1]([O:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)/[C:7](=[C:17](/[NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:6]1=[O:27])(=[O:3])[CH3:2]
Reactant: CCOC(=C1C(=O)N(OC(C)=O)c2cc([N+](=O)[O-])ccc21)c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(N/C(=C2\C(=O)N(OC(C)=O)c3cc([N+](=O)[O-])ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetoxy-3-(1-ethoxy-1-phenyl-methylidene)-6-nitro-2-indolinone and methyl 4-aminobenzoate without subsequent hydrogenation
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[C:26]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][C:17]=1[Cl:27].[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:23]3[CH2:22][CH2:21][C:20]4[CH:19]=[CH:18][C:17]([Cl:27])=[C:16]([Cl:15])[C:26]=4[CH2:25][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc2c(c1Cl)CCNCC2
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCc2ccc(Cl)c(Cl)c2CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=405 (M+ of free base). α[D]589 =-6.87 (c=0.44, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C1C=CC=CC=1.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: COc1ccccc1N
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)c1c(N)cccc1Cl
Temperature: 25 °C

Procedure:
SO2Cl2 (5.4 mL, 74 mmol, 2.5 eq) was added to a rapidly stirring solution of 2-amino-6-chlorobenzoic acid (5 g, 29.14 mmol) in benzene (146 mL) and the mixture was stirred at reflux for 24 h. The mixture was concentrated under reduced pressure, and stripped down twice with benzene to give brown oil. The resulting oil was dissolved in CHCl3 (146 mL) and to that solution was added o-anisidine and the mixture was stirred at 65° C. for 2 h. The mixture was cooled to rt and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and purified by column chromatography on a 120 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 20 min as eluent to provide 2-amino-6-chloro-N-(2-methoxyphenyl)benzamide as yellow solid. 1H NMR (DMSO-d6) δ ppm 9.44 (1 H, s), 7.86 (1 H, dd, J=7.9, 1.3 Hz), 7.13-7.21 (1 H, m), 7.04-7.11 (2 H, m), 6.97 (1 H, t, J=7.6 Hz), 6.66 (2 H, dd, J=28.0, 7.9 Hz), 5.37 (2 H, s), 3.81 (3 H, s). Mass Spectrum (ESI) m/e=277.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[F:19]C1C(F)=CC=CC=1B(O)O>>[F:1][C:2]1[C:7]([F:19])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: OB(O)c1cccc(F)c1F
Product: O=C(O)c1csc(-c2cccc(F)c2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2,3-difluorophenyl)boronic acid gave the title compound.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[Na].N[C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:12]=1[C:13]#[N:14]>CO>[N:7]1[C:11]2[C:12](=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[C:13]([NH2:14])=[N:5][C:6]=1[NH2:8]
Reactant: N=C(N)N
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Agent: O=C(O)O
Agent: [Na]
Solvent: CO
Product: Nc1ccc2nc(N)nc(N)c2c1

Procedure:
To a solution of guanidine carbonate (0.9 g, 5.0 mmol) in 30 mL methanol was added sodium (0.24 g, 10.4 mmol) and the mixture was heated under reflux for 30 minutes. The precipitated sodium carbonate was filtered off and washed with methanol. 2-Amino-5-nitrobenzonitrile (0.88 g, 5.4 mmol) was added to the methanolic solution which was then heated under reflux for additional 24 hours. The solvent was evaporated and the crude 6-nitro-2,4-quinazolinediamine subjected to catalytic hydrogenation as described in EXAMPLE 41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:29][CH2:30][CH:31]=[C:32]3[C:38]4[CH:39]=[CH:40][CH:41]=[N:42][C:37]=4[CH2:36][O:35][C:34]4[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]3=4)[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)NC1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(NC(=O)Cc3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-chloro-phenyl)-N-piperidin-4-yl-acetamide (0.2 g, 0.8 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (0.095 mL, 0.8 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/20% methanol) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].[OH-].[K+]>C(O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[F:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1ccccc1F
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2ccc(Oc3ccccc3F)nc2n1
Temperature: 4 °C
Yield: 58.2 %

Procedure:
The procedure is similar to that described in Example 37, but starting with 2-amino-7-chloro-1,8-naphthyridine (18 g), 2-fluorophenol (44.8 g) and potassium hydroxide pellets (13.2 g; 85% purity). After treatment with caustic soda and washing, the product produced (24 g; m.p. 202° C.) is dissolved in boiling ethanol (200 cc). After 16 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). 2-Amino-7-(2-fluorophenoxy)-1,8-naphthyridine (14.9 g) is produced, m.p. 206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11]Br)=[O:7])=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][N:18]=[N+:19]=[N-:20])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
A mixture of 3-(4-chlorobenzoyl)benzyl bromide (4.2 g, 13.6 mmol) and sodium azide (1.32 g, 20.3 mmol) in ethanol (40 ml) was refluxed for 5 hours, cooled to ambient temperature, and kept 16 hours. The mixture was filtered and the solids were washed twice with ethanol. The combined filtrate and washes were evaporated to dryness under vacuum and the residue was treated with diethyl ether and filtered. The filtrate was evaporated to dryness under vacuum and dried to provide 3.7 g (100%) of 3-(4-chlorobenzoyl)-benzyl azide, m.p. 43°-45° C.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[C:9]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=O)=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.[BH4-].[Na+]>N1C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]2[C:9]3[CH:10]=[CH:11][C:12]4[C:17](=[N:16][CH:15]=[CH:14][CH:13]=4)[C:8]=3[NH:7][S:3](=[O:5])(=[O:4])[N:2]2[CH3:1])=[CH:21][CH:22]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)cc2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.2 %

Procedure:
N-Methylsulfamoyl chloride (Intermediate 213) (161 mg, 1.24 mmol) was added to suspension of (8-amino-quinolin-7-yl)-(4-fluoro-phenyl)-methanone (Intermediate 367) (110 mg, 0.41 mmol) in pyridine (10 ml) and the mixture was stirred room temperature for 18 h. NaBH4 (16 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for a further 18 h. The reaction was quenched with water (20 ml) and the aqueous phase was extracted with EtOAc (30 ml). The organic phase was washed with brine (15 ml), dried (Na2SO4) and concentrated n vacuo. The crude residue was purified by column chromatography heptane/EtOAc (80:20-50:50 gradient) as the eluent to give the title compound (20 mg, 14%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[O:25])[C:21](O)=[O:22]>>[CH3:19][CH:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]([F:34])([F:35])[C:30]([F:32])([F:31])[F:33])=[O:25])[C:21]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCCC(F)(F)C(F)(F)F
Product: CC(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d), the condensation of (S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and (2RS)-2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid yielded the title compound as a white solid;
Reaction SMILES: [C:1]([Li])(C)(C)C.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:8]=12.CI>C1COCC1>[CH2:6]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:8]=12)[CH3:1]
Reactant: [Li]C(C)(C)C
Reactant: CCCc1nc2nccc(C)c2[nH]1
Solvent: C1CCOC1
Solvent: CI
Product: CCCc1nc2nccc(CC)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyllithium (0.978 mL, 1.7M/pentane) was added to a cooled (-78° C.) THF (5 mL) solution of 7-methyl-2-propylimidazo[4,5-b]pyridine (97 mg, 0.554 mmol). After 2 hour the reaction was warmed to 0° C. for 1 minute then cooled back to -78° C. MeI (0.172 mL) was added, the mixture was stirred at -78° C. for 1 hour then warmed to 0° C. for 1 minute and then quenched (NH4OH). Extractive workup and purification (SiO2, 2% MeOH/ EtOAc) gave 85 mg of 7-ethyl-2-propylimidazo[4,5-b]pyridine which was converted to the title compound as outlined in Example 7, Part B.