Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N:24](CS(C)(=O)=O)[S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([CH:34]4[CH2:36][CH2:35]4)=[CH:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1>C(O)C.O>[CH:34]1([C:21]2[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:12]3[O:11][C:10]([C:7]4[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=4)=[C:14]([C:15]([OH:17])=[O:16])[C:13]=3[CH:20]=2)[CH2:35][CH2:36]1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(CS(C)(=O)=O)S(C)(=O)=O)c(C3CC3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1cc2oc(-c3ccc(Cl)cc3)c(C(=O)O)c2cc1C1CC1

Procedure:
Potassium hydroxide (15.1 g, 270 mmol) was added to a solution of the ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate in ethanol (64 mL) and water (32 mL) under nitrogen atmosphere. The reaction was refluxed for 1 hour and then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1N HCl (250 mL) until a precipitate formed. The solid was filtered and then dried to afford 5-cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (8.7 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:14][C:15](=[O:25])[C:16]4[CH:22]=[C:21]([I:23])[CH:20]=[C:19](O)[C:17]=4[N:18]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:31]1([NH2:37])([CH:34]2[CH2:36][CH2:35]2)[CH2:33][CH2:32]1.[CH2:38](N(CC)CC)C>C1COCC1>[C:31]1([NH:37][C:15]([C:16]2[CH:22]=[C:21]([I:23])[CH:20]=[C:19]([CH3:38])[C:17]=2[NH:18][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:26]([F:28])([F:29])[F:27])[CH:11]=2)=[O:14])=[O:25])([CH:34]2[CH2:36][CH2:35]2)[CH2:33][CH2:32]1
Reactant: NC1(C2CC2)CC1
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(O)cc(I)cc12
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(I)cc(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
2.08 g (3.91 mmol) (2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-8-hydroxy-6-iodo-benzo[d][1,3]oxazin-4-one (prepared according to WO 04/067528), 0.6 g (4.50 mmol) bicyclopropyl-1-ylamine hydrochloride and 0.63 ml (4.50 mmol) triethylamine in 20 ml THF are heated 20 h at reflux. After cooling down, the precipitate is filtered and the mother liquor is evaporated. The residue is dissolved in 5 ml DMF and poured into 40 ml water. The crystals formed are filtered and purified by flash-chromatography (dichloromethane 40, diethylether 1) to afford 1.85 g title compound. 1H-NMR (CDCl3, 400 MHz. ppm): 0.11 (q, 2H), 0.45 (q, 2H), 0.62 (s, 4H), 1.4 (m, 1H), 2.10 (s, 3H), 6.50 (s, 1H), 7.40 (m, 2H), 7.51 (s, 1H), 7.77 (s, 1H), 7.85 (dd, 1H), 8.49 (m, 1H), 10.45 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:22][CH:21]([NH:23][CH3:24])[C@H:20]([CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:28])[CH2:19]1)=[O:17].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CC#N.C(N(CC)C(C)C)(C)C.CO>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:22][CH:21]([N:23]([S:36]([CH3:35])(=[O:38])=[O:37])[CH3:24])[C@H:20]([CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:28])[CH2:19]1)=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1CNC(=O)c1ccc(Cl)s1
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1CNC(=O)c1ccc(Cl)s1)S(C)(=O)=O
Reaction time: 3 h

Procedure:
To a solution of (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-methylamino-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide (example 83; 26 mg) in 0.8 ml of CH3CN and 22 μl of N,N-diisopropylethylamine was added at 22° C. 6 μl of methanesulfonylchloride and stirring was continued for 3 h. The mixture was diluted with 0.5 ml of MeOH, evaporated and the residue was chromatographed on silica (AcOEt/MeOH, 15:1) to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-(methanesulfonyl-methyl-amino)-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Colorless solid. MS 582.0 ([M+H]+)
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1.O.[NH2:38][NH2:39].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:21][C:19]([F:20])([F:22])[O:18][C:14]1[CH:13]=[C:12]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:38][N:39]=[C:24]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=4)[C:3]=3[C:4]2=[O:23])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc(C(F)(F)F)cc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethoxyphenyl)-3-(4-trifluoromethylphenylacetyl)-1,8-naphthyridine-2(1H)-one (508 mg, 1.0 mmol) produced in Synthesis Example 22 in DMF (8 mL) was added hydrazine monohydrate (purity of 80%, 194 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 5-(3-trifluoromethoxyphenyl)-3-(4-trifluoromethylbenzyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (162 mg, yield 32%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1)[C:20]([NH2:22])=[O:21].C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C)C=O>[NH2:22][C:20](=[O:21])[C@@H:19]([NH:18][C:15]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 4-(tert-Butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid, 20 g) in dimethylformamide was added (S)-2-amino-3-(4-iodophenyl)propanamide (Example 1, step (ii), 1.05 mol. eq.) and diisopropylethylamine (4 mol. eq.) at room temperature. The reaction mixture was cooled to 0-10° C. and stirred for 15 min. T3P (50% wt/wt in DMF; 1.7 mol. eq.) was added to the reaction mixture by dropwise addition at 0-10° C. over a period of 30 min and stirred for 1.5 h at the same temperature. The reaction mixture was quenched with water (2 rel. vol.) and stirred for 30 min at room temperature. 2-Methyltetrahydrofuran (15 rel. vol) and water (13 rel. vol) were added to the reaction mixture and extracted. The organic layer was separated and concentrated to 5 rel. vol. To the stirred organic portion was added toluene (10 rel. vol.) drop wise over a period of 30 min. The solution was stirred for 5 h at room temperature. The resulting solid material was filtered and washed with toluene (2 rel. vol), and dried the material at 50° C. under vacuum to afford the sub-titled compound (28.8 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:15][C:4]1[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)c2cccc([N+](=O)[O-])c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(N2CCOCC2)c2cccc([N+](=O)[O-])c2n1
Yield: 78.1 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-15, step-1 using 4-chloro-2-methyl-8-nitroquinazoline (Intermediate-27, step-2, 280 mg, 1.26 mmol), morpholine (219 mg, 2.52 mmol), and K2CO3 (521 mg, 3.78 mmol) in CH3CN (5 mL) to afford 270 mg of the title product. MS [M+H]+: 275.22.
Reaction SMILES: [CH:1](=[N:8][CH:9]=[C:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:23](C(=CC)C=O)[CH3:24]>>[CH2:11]([C:10]1([CH2:23][CH3:24])[CH2:13][CH:14]=[CH:17][CH2:18][CH2:19][CH:20]=[CH:21][CH2:16][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9]1)[CH3:12]
Reactant: NCc1ccccc1
Reactant: CCC(=CN=Cc1ccccc1)CC
Reactant: CC=C(C=O)CC
Product: CCC1(CC)C=NC(c2ccccc2)CC=CCCC=CC1

Procedure:
The procedure described in Example 1(a) is repeated, except that 93.6 g (0.5 mol) of N-benzylidene-(2-ethyl-1-butenylamine) [1-phenyl-4,4-diethyl-2-aza-1,3-butadiene, prepared from benzylamine and 2-ethyl-butenal and by subsequent isomerisation of the reaction product in the presence of potassium tert.-butylate; boiling point 70° C./7 Pa; nD20 =1.5598; cf. J. Org. Chem., 43, No. 4, 782-84 (1978)] are used. Distillation yields 116 g (0.393 mol) of 3,3-diethyl-12-phenyl-1-aza-1,5,9-cyclododecatriene; boiling point 105° C./4 Pa; nD20 =1.5369.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[C:36](=[O:39])([O-])[O-].[K+].[K+].Br[CH2:43][CH:44]1[CH2:46][O:45]1>CN(C=O)C>[OH:45][CH:44]([CH2:46][O:39][CH3:36])[CH2:43][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(O)ccc5c34)c1C)C2
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC(O)COc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3cccc(N4Cc5ccc(C)cc5C4=O)c3C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
A mixture of 7-hydroxy-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 40-2, 30 mg, 0.065 mmol) and potassium carbonate (36 mg, 0.260 mmol) in DMF (1.0 mL) was stirred at rt for 30 min, then was treated with 2-(bromomethyl)oxirane (27 mg, 0.195 mmol). The resulting mixture was heated at 90° C. for 3.5 h, cooled to rt and filtered. The filtrate was treated with methanol, stirred at rt for 2 h, then was then heated at 90° C. for 1 h. The mixture was concentrated under vacuum and purified by preparative HPLC to provide 7-(2-hydroxy-3-methoxypropoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 44-5, 4.7 mg, 13%). 1H NMR (400 MHz, methanol-d4) δ 7.83 (1 H, d, J=7.9 Hz), 7.72 (1 H, d, J=0.7 Hz), 7.46-7.52 (4 H, m), 7.38-7.45 (1 H, m), 7.04-7.12 (2 H, m), 6.99 (1 H, d, J=8.8 Hz), 6.70 (1 H, dd, J=8.7, 2.3 Hz), 4.86 (2 H, d, J=1.8 Hz), 4.03-4.22 (3 H, m), 3.53-3.65 (2H, m), 3.42 (3 H, s), 2.50 (3 H, s), 1.93 (3 H, s). Mass spectrum m/z 550.1 (M+H)+. Also isolated was 7-(3-(dimethylamino)-2-hydroxypropoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 44-6, 2.0 mg, 5%). Mass spectrum m/z 563.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:7]=2[S:6]1)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O1CCCC1>[OH:2][CH2:3][CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:7]=2[S:6]1
Reactant: COC(=O)C1CNc2ccc(C(F)(F)F)cc2S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC1CNc2ccc(C(F)(F)F)cc2S1

Procedure:
2-methoxycarbonyl-7-trifluoromethyl-3,4-dihydro-2H-[1,4]benzothiazine in 50 ml of toluene and about 10 ml of tetrahydrofuran, kept under argon. The reaction mixture is heated for 1 hour under reflux, and then after returning to 20° C. is hydrolysed with 70 ml of a saturated aqueous sodium hydrogen carbonate solution and 40 ml of ethyl acetate. The insoluble matter is removed by filtration and the filtrate is separated after settling out, the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa). The yellow oil obtained is chromatographed on 35 g of 20-45 μm silica gel contained in a column 2 cm in diameter, eluting with an ethyl acetate and cyclohexane mixture (75-25 by volume). 0.72 g of 2-hydroxymethyl-7-trifluoromethyl-3,4-dihydro-2H-[1,4]benzothiazine is thus obtained in the form of a yellow solid melting at 80° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=[O:6].Cl[Si](C)(C)[CH3:12]>CO.COC(OC)(C)C>[CH3:12][O:6][C:5](=[O:7])[C:4](=[O:8])[CH2:3][CH:2]([CH3:9])[CH3:1]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)CC(=O)C(=O)O
Solvent: CO
Solvent: COC(C)(C)OC
Product: COC(=O)C(=O)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-2-oxo-pentanoic acid (3.4 g, 26 mmol) in methanol (12 mL) and 2,2-dimethoxypropane (48 mL) is added chlorotrimethylsilane (0.38 mL). The reaction mixture is stirred at ambient temperature overnight. The reaction mixture is concentrated under reduced pressure to give the title compound as an oil, (3.8 g, quant.). 1H NMR (400 MHz, CDCl3): δ 3.86 (s, 3H), 2.72 (d, 2H), 2.16 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35][C:36](N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12]([N:14]3[CH2:36][CH2:35][C@@H:16]([OH:17])[CH2:15]3)=[O:13])[CH:19]=[CH:20][C:21]=2[CH3:22])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)N2CC[C@@H](O)C2)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (R)-(+)-3-pyrrolidinol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.31 (d, 1H, J=7.6 Hz), 7.62 (m, 2H), 7.52 (m, 2H), 7.01 (m, 2H), 5.51 (m, 2H), 4.42 (m, 1H), 3.65 (m, 4H), 2.19 (s, 3H), 2.00 (m, 2H). ESHRMS m/z 476.1175 (M+H calculated for C23H21ClF2N3O4 requires 476.1183).
Reaction SMILES: N1C=CC=CC=1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>O>[C:15]([O:14][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:17])[CH3:16]
Reactant: OCCCCCCCl
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1CCCCC1

Procedure:
Under a nitrogen atmosphere, pyridine (934 g) was added to 6-chlorohexanol (800 g). Acetic anhydride (1,200 mL) was added thereto, and after refluxing under heating for 3 hours, the reaction solution was poured into water and extracted with toluene. The organic layer was neutralized with a saturated sodium hydrogencarbonate aqueous solution, and after washing with water, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the concentrated product was purified by distillation under reduced pressure to obtain 6-acetoxycyclohexane (983 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16](C(OCC(Cl)(Cl)Cl)=O)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1CC(Sc1ccc(F)cc1)C2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccc(SC2CC3CCC(C2)N3)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-(4-fluorophenylsulfanyl)-8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo-(3.2.1)-octane (the compound of Preparation 37, 10.28 g, 24.92 mmol), 48% HBr (20 mL), and acetic acid (80 mL) was heated to 110° C. for 78 h. The reaction was adjusted to pH 11 by addition of 4 N sodium hydroxide and extracted with methylene chloride. The organic phase was filtered through Diatomaceous earth, washed with brine, dried over calcium sulfate and concentrated. The residue was kugelrohr distilled (110° C. (pot temperature), 1.5 mm Hg) to give 3.30 g of 3-(4-fluorophenylsulfanyl)-8-azabicyclo-(3.2.1)-octane as a yellow oil which had NMR δ 7.41 (dd, J=5.5, 9 Hz, 2 H), 7.00 (long range coupled t, J=8.5 Hz, 2 H), 4.11 (s, impurity), 3.55 (br t, J=3.5 Hz, 2 H), 3.24 (sym m, 1 H), 2.58 (br s, 2 H, exchanges with D2O, should integrate for 1 H), 1.90-1.77 (m, 4 H), 1.70-1.51 (m, 4 H). This product was suitable for use without further purification.
Reaction SMILES: [C:1]([N:5]([C:22](=[O:31])[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[NH:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH2:14][CH:15]([CH:17]=O)[O:16][C:11]=2[C:10]=1[CH3:21])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:40][OH:41]>CO>[C:1]([N:5]([C:22](=[O:31])[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[NH:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH2:14][CH:15]([CH:17]=[N:40][OH:41])[O:16][C:11]=2[C:10]=1[CH3:21])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C=O)CO3)C(C)(C)C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C=NO)CO3)C(C)(C)C)c1
Yield: 82.1 %

Procedure:
To a 100 mL round bottom flask, containing 100 mg (0.24 mm) of 3,5-dimethyl-benzoic acid N-tert-butyl-N′-(3-formyl-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazide, added 0.50 g of triethylamine, 70 mg (1 mm) of hydroxylamine hydrochloride and 25 mL of methanol. The reaction mixture was refluxed for 1 hour. The methanol was removed on a rotary evaporator and the residue was dissolved with chloroform and dilute HCl and transferred to a separatory funnel. The chloroform extract was dried and evaporated to dryness. The residue was chromatographed on silica and the product eluted with 40% ethyl acetate in hexane. Evaporation of solvent yielded 85 mg of 3,5-dimethyl-benzoic acid N-tert-butyl-N′-[3-(hydroxyimino-methyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl]-hydrazide. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.7 (s, 1H), 7.4 (d, 1H), 7.05 (s, 2H), 6.95 (s, 1H), 6.55 (d, 1H), 6.15 (m, 1H), 4.8 (m, 1H), 4.0-4.4 (m, 4H), 2.248 (s, 6H), 1.915 (s, 3H) 1.574 (s, 9H); TLC: Rf=0.40 (1:1 ethyl acetate:hexane).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][N:46]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[CH:47]=2)O1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:43]3[CH:44]=[N:45][N:46]([CH2:48][CH2:49][N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[CH:47]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CCN5CCOCC5)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 1F) (200 mg, 0.318 mmol) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (127 mg, 0.413 mmol) in N,N-dimethylformamide (0.79 mL) was added saturated aqueous bicarbonate solution (0.79 mL) followed by bis(triphenylphosphine)palladium dichloride (15.60 mg, 0.022 mmol). The mixture was heated to 70° C. for 4 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel, eluting with a gradient of 20% ethyl acetate in hexane to 100% ethyl acetate with 3% methanol, to afford the title compound. MS ESI(+) m/z 683.52 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BrH:13].BrBr.S([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[Br:13][CH2:11][C:10]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1)=[O:12]
Reactant: Br
Reactant: CC(=O)c1cnn(C(C)(C)C)c1
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)n1cc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1.66 g (10.0 mmol) 1-(1-tert-butyl-1H-pyrazol-4-yl)-ethanone in 18 ml dichloromethane is added 5.86 μl (0.10 mmol) of a 32% solution of hydrobromic acid in acetic acid. Then a solution of 3.20 g (20 mmol) bromine in 5 ml dichloromethane is added dropwise. The reaction mixture is stirred for 3 days at room temperature. Then aqueous sodium hydrogen sulfite is added to reduce the excess bromine. The reaction mixture is reduced in volume under vacuum and it is then partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 2-bromo-1-(1-tert-butyl-1H-pyrazol-4-yl)-ethanone as yellow oil, which crystallizes on standing; HPLC/MS 2.28 min (B), [M+H] 245/247.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2S(=O)(=O)CC1
Temperature: 55 °C
Reaction time: 7 h

Procedure:
A mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg), 4-fluorobenzyl chloride (0.090 ml), potassium carbonate (134 mg) and DMF (5 ml) was stirred at 55° C. for 7 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[(4-fluorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (162 mg) as colorless crystals.