Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])O[CH:7]=[CH:6]2.[CH3:14][N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:28]([C:25]1[CH:24]=[CH:23][C:22]([N:18]3[CH2:19][CH2:20][CH2:21][N:15]([CH3:14])[CH2:16][CH2:17]3)=[CH:27][CH:26]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(=O)occc2c1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Product: COc1ccc2c(c1)CCN(c1ccc(N3CCCN(C)CC3)cc1)C2=O

Procedure:
6-Methoxy-isochromen-1-one and 4-(4-methyl-[1,4]diazepan-1-yl)-phenylamine were reacted according to Method AC. In this way the product was obtained with molecular weight 365.48 (C22H27N3O2); MS (ESI): 366 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]([C:28]1[CH:29]=[C:30]([OH:38])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)([CH3:27])=[CH2:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:30]3[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:28]([C:25]([CH3:27])=[CH2:26])[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: C=C(C)c1cc(O)cc(C(F)(F)F)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: C=C(C)c1cc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)cc(C(F)(F)F)c1
Yield: 84.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-isopropenyl-5-trifluoromethyl-phenol (54 mg, 0.26 mmol) to give the title compound (60 mg, 85%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.Cl[CH2:13][CH2:14]Cl>>[O:11]=[C:5]([CH:13]=[CH2:14])[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: ClCCCl
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)CCC(=O)O

Procedure:
[cf. J. Chem. Soc., 3922 (1958)]. A mixture of aluminum chloride (66.7 g., 0.5 M), succinic anhydride (25 g., 0.25 M) and 1,2-dichloroethane (1 liter) in a 2 liter 3 neck flask equipped with a gas inlet tube, a mechanical stirrer and a drying tube is stirred rapidly and ethylene is bubbled in for 4.5 hours. This is poured into 900 ml. 5% hydrochlorc acid and ice. The layers are separated and the organic layer is washed with water and taken to dryness in vacuo. The aqueous layer is extracted with ether (300 ml.). This extract is washed with water and combined with the material from the original organic layer. After removal of solvent, 150 ml. of 10% potassium carbonate solution is added and the mixture is heated on a steam cone for 15 minute. After cooling, the product 4-oxo-5-hexenoic acid is extracted into ether, dried and freed of solvent in vacuo leaving 10.9 g. (34%) of brownish liquid which solidifies on standing. This is distilled to give 7.1 g. (22%) of colorless liquid which solidifies on standing, b.p. ~120°-130°/0.5 mm.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[C:12]2[N:11]=[CH:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)n1cnc2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1cnc2c(N)cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 1,1-dimethylethyl 4-nitro-1H-benzimidazole-1-carboxylate (0.95 g, 3.6 mmol) in ethanol (20 mL) was added 10% palladium carbon (0.10 g), and the mixture was stirred under hydrogen atmosphere at room temperature for 4 hours. The reaction solution was filtered through a Celite, the Celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure to obtain the title compound (0.84 g, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([F:35])[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl.Cl>[Cl:28][C:27]1[C:22]([NH:21][C:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH3:11])[CH:6]=2)=[O:14])=[CH:23][C:24]([F:35])=[C:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:26]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Reactant: Cn1cc(C(=O)O)c2cc(F)ccc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2cn(C)c3ccc(F)cc23)cc1F
Temperature: 0 °C
Yield: 46.6 %

Procedure:
In methylene chloride (30 ml) was dissolved 5-fluoro-1-methylindole-3-carboxylic acid (885 mg, 4.58 mmol). To the resulting solution was added oxalyl chloride (600 μl, 6.87 mmol) under stirring at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. From the reaction mixture, the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (50 ml). The resulting solution was added dropwise to a solution of ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (1.06 g, 4.58 mmol) in methylene chloride (20 ml), followed by heating under reflux for 15 minutes. The reaction mixture was cooled and triethylamine (3.19 ml, 22.9 mmol) was added thereto. The resulting mixture was heated under reflux for 18 hours. The reaction mixture was cooled and poured in 1N HCl, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane/ethyl acetate (2/1) eluate fractions, ethyl (5-chloro-2-fluoro-4-(((5-fluoro-1-methyl-3-indolyl)carbonyl)amino)phenyl)acetate (868 mg, 47%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:24])=[C:4](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.N12CCCN=C1CCCCC2.O.[N+:37]([CH3:40])([O-:39])=[O:38]>>[Cl:1][C:2]1[C:3]([F:24])=[C:4]([CH:17]([CH2:40][N+:37]([O-:39])=[O:38])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:8]2([CH3:13])[O:9][CH2:10][CH2:11][O:12]2)[CH:7]=1
Reactant: CCOC(=O)/C=C/c1c(F)c(Cl)cc(C2(C)OCCO2)c1OCC
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)CC(C[N+](=O)[O-])c1c(F)c(Cl)cc(C2(C)OCCO2)c1OCC
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A solution ethyl (2E)-3-[3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl\) phenyl]acrylate (10 g, 28 mmol) (from Step 2) in nitromethane (100 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 mL, 31 mmol) and stirred at 60° C. for 15 h. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude orange oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-30%) to give the desired product as a mixture of enantiomers (10.4 g, 89%). 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=9.1 Hz, 1H), 4.82 (ddd, J=12.5, 7.6, 1.4 Hz, 1H), 4.68 (dd, J=12.5, 7.2 Hz, 1H), 4.54-4.40 (m, 1H), 4.15-3.90 (m, 6H), 3.89-3.75 (m, 2H), 2.85 (ddd, J=16.0, 8.6, 1.4 Hz, 1H), 2.73 (dd, J=16.1, 6.2 Hz, 1H), 1.70 (s, 3H), 1.47 (t, J=7.0 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H). LCMS for C18H24ClFNO7 (M+H)+: m/z=420.1; Found: 420.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)C(Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
A mixture of 1 g of 2-(tert-butoxycarbonylamino)-3-(4-cyanophenyl)propionic acid and 0.540 g of diisopropylamine in 10 ml of DCM is cooled to 0° C., 0.960 ml of triethylamine is added, followed by addition of 1.76 g of bromotripyrrolidinophosphonium hexafluorophosphate, and the mixture is stirred for 2 hours and allowed to warm to RT. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with water, with 5% KHSO4 solution, with water, with saturated NaHCO3 solution and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a heptane/EtOAc mixture (80/20; v/v). 0.4 g of the expected product is obtained; m.p.=172° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH2:34][CH2:35][NH2:36])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH2:34][CH2:35][NH:36][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCN1CCCCC1CN1CCCCCC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCCC2CN2CCCCCC2)c2ccccc21
Yield: 39 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(hexahydro-1H-azepin-l-yl)methyl]-piperidin-l-yl]ethanamine in a yield of 39% of theory. Colourless crystals, m.p. 156°-158° C. (acetonitrile).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[C:8](=[O:13])[CH:7](Br)[C:6]=2[CH:15]=1.CS(C)=[O:19]>>[Br:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[C:8](=[O:13])[C:7](=[O:19])[C:6]=2[CH:15]=1
Reactant: CS(C)=O
Reactant: O=C1C2CC(C2)c2cc(F)c(Br)cc2C1Br
Product: O=C1C(=O)C2CC(C2)c2cc(F)c(Br)cc21
Yield: 72 %

Procedure:
A solution of 2,9-dibromo-3-fluoro-6,7-dihydro-5H-5,7-methanobenzo[7]annulen-8(9H)-one (1.04 g at 65% purity LC-UV215) in dimethylsulfoxide (15 mL) was warmed to 80° C. for 1 hr. Evaporation of the reaction mixture (high vacuum distillation) furnished the crude title compound (0.87 g at 72% purity LC-UV215) as a golden-brown syrup which was carried through to the next synthetic step without purification. 1H NMR (500 MHz, CDCl3) δ 2.25-2.30 (m, 2H), 3.12-3.18 (m, 2H), 3.48-3.51 (m, 1H), 3.61-3.65 (m, 1H), 6.94 (d, J=8.2 Hz, 1H), 8.55 (d, J=6.6 Hz, 1H); M+1=305/307.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH:12]1[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=[C:10]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:11]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Yield: 100.7 %

Procedure:
A mixture of 43.5 g of p-chlorothiophenol, 47.1 g of p-chloronitrobenzene, 39.0 g of sodium carbonate, 120 ml of water and 150 ml of ethanol was heated at 100° C. for 19 hours, giving 80.0 g of 4-chloro4'-nitrodiphenylsulfide, which was then dissolved in a mixture of 400 ml of acetic acid and 100 ml of 30% hydrogen peroxide and stirred at 100° C. for one hour, giving 80.2 g of the corresponding sulfonyl derivative.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:37])=[CH:23][CH:22]=2)[C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:37])=[CH:23][CH:22]=2)[C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Reaction time: 1 h

Procedure:
640 μl (7.4 mmol) of trifluoroacetic acid were added dropwise to a solution of 300 mg (0.740 mmol) of tert-butyl(+)-cyclopentyl{4-[(1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-ethanoate in 1.5 ml dichloromethane. After 1 h of stirring, the reaction mixture was concentrated under reduced pressure and the residue was dried under high vacuum. This gave 267 mg (100% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C1C[O:28][CH2:27]C1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH:27]=[O:28])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nccs1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-tert-butyloxycarbonylaminothiazole (88.0 g, 439 mmol) in THF (1760 ml) was added dropwise a 1.59M solution of n-butyllithium in hexane (729 ml, 1159 mmol) over 20 minutes at −78° C., and the mixture was warmed to −10° C. over 1 hour. The mixture was cooled again to −78° C. and thereto was added DMF (102 ml, 0.132 mmol) in one portion. The acetonedry ice bath was removed. The mixture was stirred for 30 minutes, and then poured into cold water (1000 ml) and thereto was added ethyl acetate (2000 ml). The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate and the solvents were removed. The residue was recrystallized from ethyl acetate to give 2-tert-butyloxycarbonylaminothiazole-5-carbaldehyde (74.8 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:8]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.CCO[C:28]([C:30]([NH2:32])=[O:31])=[O:29].Cl>CCO>[C:28]1(=[O:29])[N:32]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[NH:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[C:8]=3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:5][CH2:6]2)[C:30]1=[O:31]
Reactant: CCOC(=O)C(N)=O
Reactant: Fc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: Cl
Solvent: CCO
Product: O=c1c(=O)n1N1CCC(c2[nH]nc(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Reaction time: 16 h

Procedure:
To a suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole (Example C-2) (0.11 g, 0.35 mmol) in 2 mL EtOH was added ethyl acetamidate hydrochloride (0.065 g, 0.53 mmol) and the mixture was refluxed for 30 minutes. The solution was left at 5-10° C. for 16 h and filtered to obtain the title compound as a white solid: MS (M+H): 364 (base peak).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:21])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>ClCCl>[Si:1]([O:8][CH2:9][CH:10]([O:21][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][O:22]1)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(C)(C)c1ccc(C(O)CO[Si](C)(C)C(C)(C)C)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(CO[Si](C)(C)C(C)(C)C)OC2CCCCO2)cc1
Reaction time: 2 h

Procedure:
1-Tert-butyldimethylsilyloxy-2-hydroxy-2-(4-tert-butylphenyl)ethane (0.5 g, 1.622 mmol) is dissolved in dichloromethane and to it is added dihydropyran (0.163 g, 1.94 mmol) and toluenesulfonic acid (33 mg, 0.194 mmol). The reaction is stirred for 2 hours after which the mixture is washed with water and dried. The crude residue obtained after concentration is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to obtain the product.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.N.[CH3:40][OH:41]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([O:41][CH3:40])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: CO
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: N
Product: COc1nccc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1

Procedure:
Starting material: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and 2M ammonia in methanol.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:25][C:26]#[N:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O>CN(C=O)C>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:25][C:26]#[N:27])[CH2:20][CH2:21][N:22]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:23][CH2:24]4)[CH:18]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCNCC4)c3)n2)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCN(CC(F)(F)F)CC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.7 %

Procedure:
2-(4-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-4-yl)acetonitrile hydrochloride (Example 28, Step A; 0.050 g, 0.11 mmol) was dissolved in DIEA (0.12 mL, 0.70 mmol) and DMF (0.2 mL) with sonication. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.025 g, 0.11 mmol) was added and the reaction was stirred at ambient temperature. After four hours the reaction was applied to a silica caplet and pumped to dryness. The caplet was applied to a silica column and eluted with 0.5-2% MeOH/DCM. The purified product was isolated to provide 2-(4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)acetonitrile (5.0 mg, 10% yield) as a solid. MS (apci) m/z=470.2 (M+H).
Reaction SMILES: [NH:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[S:3].Br[CH2:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=O>O>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:4]=[C:2]([NH:1][C:5]3[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=3)[S:3][CH:17]=2)[CH:21]=1
Reactant: CCOC(=O)c1ccc(NC(N)=S)cc1
Reactant: O=C(CBr)c1cccnc1
Solvent: O
Product: CCOC(=O)c1ccc(Nc2nc(-c3cccnc3)cs2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 166.2 %

Procedure:
Ethyl 4-thioureidobenzoate (209 mg, 0.935 mmol) was added to a warm solution (50° C.) of 2-bromo-1-(pyridin-3-yl)ethanone (250 mg, 0.88 mmol) in water (5 mL) and stirred at 50° C. for 5 h. The precipitated was filtered out to afford the title compound 428 as a yellow solid (476 mg, wet) which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[CH:20]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:22][CH:23]1[CH2:36][C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[N:33]=3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:38][O:37][C:32]1[N:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][C:26]1[O:25][CH2:24][CH:23]([CH2:22][N:1]3[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]4[CH:11]=[CH:12][C:13]5[S:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=5[CH:20]=4)=[O:9])[CH2:3][CH2:2]3)[CH2:36][C:35]2=1
Reactant: O=C1CSc2ccc(C(=O)NC3CCNCC3)cc2N1
Reactant: COc1ccc2ncc3c(c2n1)CC(CBr)CO3
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc3c(c2n1)CC(CN1CCC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3
Temperature: 80 °C
Reaction time: 24 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid piperidin-4-ylamide (56 mg, 0.16 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-oxa-5,9-diaza-phenanthrene (50 mg, 0.16 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by N,N-diisopropylethylamine (30 μL, 0.17 mmol, 1.1 eq). After 24 hours stirring at 80° C., solvent is removed and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [1-(6-methoxy-3,4-dihydro-2H-1-oxa-5,9-diaza-phenanthren-3-ylmethyl)-piperidin-4-yl]-amide as an off-white lyophilized powder (39 mg, 47% yield).
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[N+:8]([O-])=[C:7]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:6]=12>CO>[CH3:3][O:4][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[N:8]=[C:7]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:6]=12
Reactant: COC(=O)c1c(OC)c2c([n+]([O-])c1C)CCCCC2
Reactant: [H][H]
Solvent: CO
Product: COC(=O)c1c(C)nc2c(c1OC)CCCCC2
Yield: 99.5 %

Procedure:
Methanol (5.0 ml) was added to Raney nickel water suspension (0.2 ml) and stirred at room temperature for 30 minutes in an atmosphere of hydrogen. The reaction solution was mixed with methanol solution (6.0 ml) of methyl 4-methoxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate N-oxide (607.9 mg, 2.29 mmol) and stirred at room temperature for 30 hours in an atmosphere of hydrogen. After removal of the catalyst by filtration, the resulting residue was washed with methanol, the solvent was evaporated under reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by a silica gel column chromatography (ether:hexane=2:1) to obtain the title compound (567.8 mg, 99.6%) as colorless oil.