Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=O)#[N:2].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:10][C:9]1[N:8]=[C:6]([C:5]2[CH:4]=[C:3]([CH:32]=[CH:31][CH:30]=2)[C:1]#[N:2])[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(C#N)c3)nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(C#N)c4)n3n2)cc(OC)c1OC

Procedure:
In a similar manner as described for Example 1,3-cyano-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 17) (0.12 g, 0.25 mmol) in 1,2-dichloroethane (20 mL) and phosphorus oxychloride (0.28 mL, 3.0 mmol) gave 3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}benzonitrile (0.023 g) as a yellow solid. 1H NMR (CDCl3): δ8.84 (s, 1H), 8.79 (d, J=8.1 Hz, 1H), 8.74 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.54 (dd, J=7.9, 7.8 Hz, 1H) 7.09 (s, 1H), 6.83 (s, 2H), 3.85 (s, 3H), 3.81 (s, 6H), 2.60 (s, 3H). MS m/z 417 (M+1).
Reaction SMILES: [CH3:1]OCCO[AlH2-]OCCOC.[Na+].[C:13]([C:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[C:26]([NH:27][C:28](C)(C)C3C=CC=CC=3)[C:21]2=[N:20][C:19]=1[CH3:37])(OCC)=[O:14].[C:38]1([CH3:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:44][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:1])[C:39]=1[CH2:28][NH:27][C:26]1[C:21]2[N:22]([C:18]([CH2:13][OH:14])=[C:19]([CH3:37])[N:20]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1c(C)nc2c(NC(C)(C)c3ccccc3)cccn12
Reactant: COCCO[AlH2-]OCCOC
Agent: [Na+]
Product: Cc1cccc(C)c1CNc1cccn2c(CO)c(C)nc12
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A solution of vitride (40 ml, 136 mmol) in toluene (25 ml) was added dropwise to a nitrogen-purged solution of 3-carboethoxy-8-(dimethylbenzylamino)-2-methylimidazo[1,2-a]pyridine (8.0 g, 23.71 mmol) in toluene (100 ml). The ice-bath was removed and the reaction mixture was stirred at room temperature for 105 min. The reaction mixture was cooled to 0° C. and quenched by addition of water (36 ml). The mixture was filtered and the organic layer washed with aqueous NaHCO3, dried over Na2SO4 and concentrated. Acetonitrile (20 ml) was added and the product was collected by filtration. The crystalline product was washed twice with acetonitrile and dried in vacuo. Yield 5.6 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]([F:12])([F:11])[F:10])[C:3]=1[F:13].C(Cl)(Cl)(Cl)Cl.C(#N)C.I([O-])(=O)(=O)=[O:23].[Na+].[OH2:28]>[Ru](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([C:9]([F:11])([F:12])[F:10])(=[O:23])=[O:28])[C:3]=1[F:13]
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Fc1c(Br)cccc1SC(F)(F)F
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=S(=O)(c1cccc(Br)c1F)C(F)(F)F

Procedure:
Preparation according to preparation 4: 1-bromo-2-fluoro-3-[(trifluoromethyl)thio]benzene (0.37 g), carbon tetrachloride (4 ml), acetonitrile (4 ml), water (8 ml), sodium periodate (0.86 g), ruthenium trichloride (1 mg). Yield: 0.3 g. MS m/z (rel. intensity, 70 eV) 308 (M+, 18), 306 (M+, 19), 239 (57), 173 (60), 94 (bp).
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([CH3:12])[CH:6]=1)C.C([Li])CCC.[CH:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22]>C(OCC)C.CCCCCC>[CH3:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[OH:22])[CH:4]=[O:13]
Reactant: CCOC(OCC)c1ccc(Br)c(C)c1
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(C=O)ccc1C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 76.7 %

Procedure:
To a solution of 1.88 g of 4-bromo-3-methylbenzaldehyde diethylacetal in 20 ml of diethyl ether was added dropwise 5.0 ml of a 1.4 M solution of butyllithium in hexane at -70° to 0° C., and the mixture was stirred at 0° to -50° C. for 50 minutes. To it was added dropwise 0.89 g of 3-formylpyridine at -30° to -20° C., and the reaction mixture allowed to warm to room temperature with stirring. After concentration under reduced pressure the residue was stirred with 10 ml of tetrahydrofuran and 10 ml of 2 N hydrochloric acid at room temperature for 45 minutes. The reaction mixture was basified with sodium bicarbonate, extracted with diethyl ether, and the extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:2) as eluent to give 1.20 g of the title compound having the following physical characteristics:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][C@@H:27]1[CH2:31][NH:30][CH2:29][C@H:28]1[NH:32]C(=O)OC(C)(C)C>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][C@@H:27]([F:26])[C@H:28]([NH2:32])[CH2:29]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H]1F
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@@H](N)[C@H](F)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 78-1 in Scheme 7 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.71, 1.89 Hz, 1 H), 7.91-7.75 (m, 2 H), 7.62 (t, J=7.45 Hz, 1 H), 7.52 (d, J=8.59 Hz, 1 H), 7.45 (td, J=7.58, 3.28 Hz, 1 H), 7.32 (d, J=8.59 Hz, 1 H), 6.19 (s, 1 H), 5.18 (brs, 2 H), 5.06 (m, 1 H), 4.53 (brs, 2 H), 4.17 (m, 1 H), 4.03 (dd, J=9.98, 5.43 Hz, 1 H), 3.81-3.54 (m, 4 H), 3.45-3.35 (m, 1 H), 2.42 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:30]([OH:32])C>>[ClH:17].[CH3:30][O:32][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Cc1ccccc1COc1cccnc1N
Reactant: CCO
Agent: Cl
Product: COc1ccc(COc2cccnc2NC(=N)Cc2ccccc2)cc1

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (4.6 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 26 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product (0.75 g), m.p. 188°-192° C.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1.[CH2:24]([CH:27]1[CH2:29][O:28]1)[CH2:25][CH3:26].O>C1COCC1>[OH:28][CH:27]([CH2:24][CH2:25][CH3:26])[CH2:29][O:3][C@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Reactant: CCCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(O)CO[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
NaH (25 mg, 70% in oil, 0.7 mmol) was added to a solution of (6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step e) (300 mg, 1 mmol) in anhydrous THF (10 mL), the mixture was stirred at room temperature for 0.5 hour, then 2-propyloxirane (300 mg, 3.5 mmol) was added to the solution, the mixture was stirred at 75° C. overnight in a sealed tube. The mixture was cooled and poured into water (50 mL), extracted with ethyl acetate (3×30 mL), the organic layers was combined and washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate=4:1) to yield 100 mg (26%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.62 (d, 2H, J=8.7 Hz), 7.19 (d, 2H, J=8.7 Hz), 4.20 (t, 1H, J=5.7 Hz), 4.09-4.00 (m, 3H), 3.82-3.74 (m, 2H), 3.52-3.43 (m, 1H), 3.37-3.18 (m, 2H), 2.26-2.10 (m, 2H), 1.60-1.38 (m, 5H), 0.96 (t, 3H, J=6.9 Hz); LC-MS: 389.1 [M+1]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[OH:13])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[N+:10]([C:6]1[C:5]2[O:13][CH:2]([CH2:3][OH:19])[CH2:1][C:4]=2[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cccc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2c1OC(CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a solution of 2-nitrophenol (13.9 g, 100 mmol) in N,N-dimethylformamide (300 mL) was added with sodium hydride (4.2 g, 100 mmol 60%) followed by allyl bromide (13.3 g, 110 mmol) and the reaction was allowed to stir at room temperature for 2 hours The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 1-(allyloxy)-2-nitrobenzene. The oil was re-dissolved in mesitylene (500 mL) and heated at reflux for 3 d. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, dichloromethane:hexanes 0.5:9.5) provided 6.8 g, (50%) of 2-allyl-6-nitrophenol as a yellow oil. To a solution of 2-allyl-6-nitrophenol (6.6 g, 36.84 mmol) in dichloromethane (300 mL) was added 3-chloroperoxybenzoic acid (77%, 16.5 g, 73.67 mmol) The reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was washed with a 1:1 solution of 10% sodium sulfite:saturated sodium bicarbonate (2×300 mL). The solvent was removed in vacuo to give crude yellow oil. The oil was diluted with methanol (300 mL) and added to a solution of potassium carbonate (15.0 g, 108.5 mmol) the solution was allowed to stir at room temperature 2 h. The solvent was removed in vacuo. The residue was washed with water (1000 mL) and ethyl acetate (500 mL). The aqueous layer was acidified with 1 N aqueous hydrogen chloride and washed with ethyl acetate (500 mL). The combined organics were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate) and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, dichloromethane:hexanes 4:10) provided 3.18 g (44%) of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol as yellow solid. mp 63-65° C.
Reaction SMILES: [Br-].[CH:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCCCCC.[CH2:40]([O:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[N:59]=[CH:58][C:57]([CH:60]=O)=[CH:56][N:55]=2)=[CH:50][CH:49]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>COC(C)(C)C.O1CCCC1>[CH:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:60][C:57]2[CH:58]=[N:59][C:54]([C:51]3[CH:52]=[CH:53][C:48]([O:47][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:49][CH:50]=3)=[N:55][CH:56]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCCCCOc1ccc(-c2ncc(C=O)cn2)cc1
Reactant: c1ccc([P+](CCCCCCCCC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: CCCCCCCOc1ccc(-c2ncc(C=CCCCCCCCC3CCCC3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3.7 g of (8-cyclopentyl-octyl)-triphenylphosphonium bromide (prepared by heating 3.4 g of (8-bromooctyl)-cyclopentane and 3.9 g of triphenylphosphine in 15 ml of toluene overnight and precipitation of the product from the cooled reaction mixture by addition of hexane) in 20 ml of tert.-butyl methyl ether is treated with 0.8 g of potassium tert.-butylate and the yellow suspension is stirred at room temperature for 45 minutes. Then, a solution of 1.64 g of 2-(4-heptyloxy-phenyl)-pyrimidine-5-carboxaldehyde in 10 ml of tetrahydrofuran is added dropwise at 0° to 5° C. The reaction mixture is stirred at 0° C. for a further 2 hours and then triturated with 10 ml of saturated sodium hydrogen carbonate solution. The phases are separated and the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue is partitioned between methanol/water (vol.) 4:1 and hexane and the methanol phase is separated. The hexane phase is washed with methanol/water 4:1 and the filtrate is concentrated. The crude 5-(9-cyclopentyl-non-1-enyl)-2-(4-heptyloxy-phenyl)-pyrimidine obtained is purified by chromatography on 10 g of silica gel with hexane/ethyl acetate 19:1 (v/v).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][CH2:16][CH2:17][C@@H:18]1[CH2:24][N:23]([CH3:25])[C:22](=O)[C:21]2[CH:27]=[CH:28][CH:29]=[N:30][C:20]=2[O:19]1.C1(C)C=CC=CC=1>C(#N)C>[Cl:15][CH2:16][CH2:17][C@@H:18]1[CH2:24][N:23]([CH3:25])[C:22](=[S:2])[C:21]2[CH:27]=[CH:28][CH:29]=[N:30][C:20]=2[O:19]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1C[C@@H](CCCl)Oc2ncccc2C1=O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN1C[C@@H](CCCl)Oc2ncccc2C1=S

Procedure:
To a suspension of 9 g (0.02 mole) of phosphorus pentasulfide in 75 ml of acetonitrile was added 18 g (0.075 mole) of (R)-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido [3,2-f]-1,4-oxazepine-5(4H)-one and the mixture was stirred at reflux for 2.5 hr, cooled and treated with 60 ml of toluene. The mixture was filtered and the solid washed twice with 30 ml of 25% acetonitrile-75% toluene. The volume was made to about 400 ml with 50% toluene-50% acetonitrile and extracted with saturated aqueous potassium bicarbonate. The organic layer was separated, treated with magnesium sulfate and charcoal, and filtered. The filtrate was concentrated and the residue was recrystallized from isopropyl alcohol-chloroform. Yield of title compound was 13 g (68%), m.p. 168°-170° C.; [α]D25 =(-)47.4 (chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([O:15][CH3:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C.CC(N(C)C)=O>[CH2:13]([O:12][C:10]1[C:9]([O:15][CH3:16])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]=[CH:19][N:20]([CH3:22])[CH3:21])[CH:11]=1)[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CCOc1cc(N)c(C(=O)OC)cc1OC
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1OC
Temperature: 100 °C
Yield: 97.1 %

Procedure:
A mixture of 15.056 g (66.9 mmol) methyl 2-amino-4-ethoxy-5-methoxybenzoate and 14.1 ml (100 mmol) N,N-dimethylformamide dimethylacetal was heated to 100° C. under N2. At 4.5 hours added 4.7 ml (33.3 mmol) more DMF/DMA and removed heat at 5 hours. Stripped solvent, azeotroped with toluene, and dried in vacuo, giving 18.211 g of grey-brown solid: mass spectrum (electrospray m/e): M+H=281.3.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:18]>[OH-].[Na+].O>[CH3:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([S:1][NH2:18])[S:6][N:5]=1
Reactant: [NH4+]
Reactant: Cc1ccccc1-c1nsc(S)n1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: Cc1ccccc1-c1nsc(SN)n1

Procedure:
A solution of 56 g of 5-mercapto-3-(2-methylphenyl)-1,2,4-thiadiazole in 870 ml of 5% sodium hydroxide and 130 ml of water and a solution of 280 ml of 10% NaOCl diluted to 1000 ml with water were added dropwise to 2260 ml of an ammonium hydroxide solution while the mixture was stirred and maintained at 0° with an ice/methanol bath. The resulting mixture was stirred for 10 more minutes and the solids were collected, washed with water and dried under high vacuum (P2O5) to give 43 g of solid, m.p. 110°-112° C.
Reaction SMILES: [C@H:1]1([NH2:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21]>CN(C=O)C>[NH2:10][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][C@H:1]2[NH:11][C:20](=[O:21])[NH:19][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:6]=1
Reactant: Nc1ccc2c(c1)[C@H](N)CC2
Reactant: CCOC(=O)CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)N[C@@H]1CCc2ccc(N)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
(R)-2,3-dihydro-1H-indene-1,6-diamine (1 eq, 100 mg, 0.46 mmol) and triethylamine (2.5 eq, 158 μL, 1.15 mmol) were dissolved in 2 mL of DMF. The reaction mixture was cooled at 0° C. and ethyl isocyanatoacetate (1 eq, 59 mg, 51 μL, 0.46 mmol) was added dropwise and stirred for 2 hours at 0° C. The reaction mixture was concentrated and purified on reverse phase (H2O/MeCN) to afford the compound 46 (26 mg, 21%) as a white solid Rf=0.26. 1H NMR (300 MHz, DMSO): δ 6.91 (d, J=7.8, 1H), 6.47-6.39 (m, 2H), 6.36 (d, J=8.3 Hz, 1H), 6.11 (t, J=5.9 Hz, 1H), 5.02-4.88 (m, 3H), 4.13 (q, J=7.1 Hz, 2H), 3.83 (d, J=6.0, Hz 2H), 2.87-2.57 (m, 2H), 2.40-2.25 (m, 1H), 1.72. 1.56 (m, 1H), 1.31-1.17 (t, J=7.2 Hz, 3H). HPLC method A tr=5.60 nm (93.4%). ESI-MS m/z: 278.2 [M+H]+.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:5][C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22](C(OC(C)(C)C)=O)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:6]1[NH:7][C:8](=[O:11])[C:9]2[S:10][C:2]([C:24]3[CH:23]=[N:22][NH:21][C:20]=3[CH3:19])=[CH:3][C:4]=2[N:5]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1[nH]c(-c2ccccc2Cl)nc2cc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2nc(-c3ccccc3Cl)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
6-Bromo-2-(2-chlorophenyl)thieno[3.2-d]pyrimidin-4(3H)-one (157 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (425 mg), sodium carbonate (138 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (38 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 1 hr, 8M aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at 100° C. for 30 min. After stirring, the mixture was extracted with ethyl acetate/tetrahydrofuran mixture, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (43 mg) as a yellow solid.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=O)[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1.[NH2:25][C:26]([CH:33]([CH3:35])[CH3:34])=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)CO>[CH:33]([C:26]1[NH:25][C:14]([CH:15]([CH3:17])[CH3:16])=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH3:35])[CH3:34]
Reactant: CCOC(=O)C=C(N)C(C)C
Reactant: CC(C)C(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Solvent: CC(=O)O
Solvent: OCCO
Product: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(c2ccccc2)C1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
2.86 ml (50 mmol) of glacial acetic acid are added to 13.45 g (50 mmol) of the compound from Example 97 and 17.4 g (100 ml) of ethyl 3-amino-4-methyl-pent-2-enoate in 80 ml of ethylene glycol and the mixture is heated to reflux overnight. After cooling to room temperature, it is concentrated in vacuo and the residue is dissolved in dichloromethane and extracted several times using water. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is taken up in ethyl acetate. After extracting using 10% strength hydrochloric acid, water and saturated sodium hydrogen carbonate solution, the organic phase is dried again and concentrated, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether)).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:35]3=[N:36][CH:37]=[N:38][C:39]([O:40][CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[C:34]3[CH:33]=[N:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(N(CC)CC)C>CN(C=O)C>[CH:13]1([O:19][C:1]([N:44]2[CH2:45][CH2:46][CH:41]([O:40][C:39]3[N:38]=[CH:37][N:36]=[C:35]4[N:31]([C:28]5[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:23])=[O:24])=[CH:26][CH:27]=5)[N:32]=[CH:33][C:34]=34)[CH2:42][CH2:43]2)=[O:2])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)OC5CCCCC5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Carbonyldiimidazole (0.28 mmol, 46 mg), and cyclohexanol (0.28 mmol, 34 μL) were dissolved in DMF (2 mL) and stirred for 30 minutes at room temperature. Then, 1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride salt (0.16 mmol, 60 mg) and triethylamine (0.84 mmol, 118 μL) were added and continued to stir at 60° C. for 24 hours. The reaction mixture was quenched with water followed by an extraction with ethylacetate. Removal of organic solvents in vacuo and purification by HPLC provided compound A63 as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.67 (s, 1H); 8.61 (d, 2H); 8.26 (s, 1H); 8.11 (d, 2H); 5.62 (h, 1H); 4.71 (h, 1H); 3.91 (m, 2H); 3.38 (m, 2H); 3.10 (s, 3H); 2.10 (m, 2H); 1.87 (m, 4H), 1.65 (m, 6H); 1.28 (m, 2H). LCMS (ESI), m/z 500.4 (MH+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C:21]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Product: COc1cc(OC)cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
The method of example 3.1 was used with 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1 mmol) and 3,5-dimethoxy-benzoyl chloride (1 mmol) to prepare the title compound. Chromatography on silica gel eluting sequentially with ethyl acetate and then 6% methanol in dichloromethane gave the title compound.