Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([O:18]C)=[O:17])=[C:4]([F:20])[CH:3]=1.C1COCC1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=[O:17])=[C:4]([F:20])[CH:3]=1
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
The product from Step 1 (503 mg, 1.70 mmol, 1.00 equiv) was dissolved in 3/1 MeOH:THF (8 mL total). Following addition of 2.5N NaOH (2 mL), the reaction mixture was heated to 60° C. for 6 hours, then stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed again with 1N NaOH. The aqueous phases were combined and acidified to pH˜1 with 5N HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with satd. NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated en vacuo and azeotroped several times with hexanes to afford 252 mg (52%) of the acid as an off-white solid. MS (ES+) m/e 284 [M+H]+.
Reaction SMILES: [CH:1](Br)=[CH2:2].[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[NH4+].[Cl-]>C1COCC1.BrBr.O>[OH:10][CH:9]([C:8]1[CH:11]=[CH:12][C:5]([OH:4])=[CH:6][CH:7]=1)[CH:1]=[CH2:2]
Reactant: C=CBr
Reactant: O=Cc1ccc(O)cc1
Agent: BrBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)c1ccc(O)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A 2.5 l sulfonation flask equipped with stirrer, thermometer, reflux condenser, addition funnel and bubble counter connected to an argon flask is charged with 92.2 g Mg turnings, (4.0 mol) and 150 ml THF. After the system has been flushed with argon one iodine crystal is added followed by 30 drops of a solution of 192.6 g vinyl bromide (1.8 mol) in 300 ml THF. Using an oil bath, the reaction flask is heated to 70° C. and one drop of bromine is added. After ignition of the Grignard-reaction the oil bath is removed and the vinyl bromide-THF solution is added steadily at ambient temperature over a period of 6 hours. Stirring is continued for another 30 minutes and the cloudy, black-grey mixture obtained is cooled to 0° with an ice bath. After dilution with 600 ml THF, a solution of 61.05 g 4-hydroxy-benzaldehyde (0.5 mol) in 150 ml THF is added under efficient cooling (ice bath) over a period of 30 minutes. The thick, but stirrable suspension obtained is stirred at room temperature overnight and then cooled to 0° C. Under vigorous stirring a solution of 133.7 g NH4Cl (2.5 mol) in 350 ml H2O is added very carefully over a period of 1.5 hours. suspension obtained is stirred for another 1.5 hours, the precipitated solids are separated by filtration and the reaction vessel is rinsed several times with a total of 600 ml MTBE. The combined organic layers are washed 2× with 500 ml water, 2× with 500 ml aq. NaHSO3 (10%), 2× with 500 ml H2O, 1× with 500 ml saturated. NaHCO3 and 2× with 500 ml brine/water ca 2:1. Each aqueous phase is extracted 1× with 500 ml MTBE, the combined organic phases are dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel 60, Merck Flash; 30 cm column with 7.5 cm diameter; solvent: hexane/MTBE 1:1) to give 56.0 g (75%) 4-(1-hydroxyallyl)-phenol in the form of a yellowish, viscous oil that slowly crystallizes.
Reaction SMILES: [Br:1][C:2]1(C=O)CC=C[S:3]1.C[Si](C)(C)[C:11]([F:14])([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Br:1][C:2]1[S:3][C:37]([CH:36]([OH:35])[C:11]([F:14])([F:13])[F:12])=[CH:38][CH:39]=1
Reactant: O=CC1(Br)CC=CS1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OC(c1ccc(Br)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 36 h
Yield: 98 %

Procedure:
To a solution of 2-bromo-2-thiophenecarboxaldehyde (2.1 g, 0.01 mol) and trimethyl(trifluoromethyl)silane (1.7 g, 0.012 mol) in dry tetrahydrofuran at 0° C. was added tetrabutylammonium fluoride (10 mL of 1.0 M tetrahydrofuran solution, 0.01 mol) drop wise. The mixture was warmed to room temperature and stirred for 36 hours. The reaction was then quenched with 6N HCl and stirred for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give 3.3 g of crude as a dark brown oil, which was purified through a plug of silica gel eluting with an ethyl acetate and hexane mixture (1:1) to give 2.56 g of the title compound as a yellow liquid (98% yield), 1H NMR (300 MHz, CDCl3) δ ppm 2.78 (d, J=5.15 Hz, 1H) 5.14-5.27 (m, 1H) 6.95 (d, J=3.68 Hz, 1H) 7.00 (d, J=3.68 Hz, 1H),
Reaction SMILES: [NH2:1][C:2]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:9](O)=[O:10]>O>[C:7]([C:2]1([NH:1][CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3]1)#[N:8]
Reactant: N#CC1(N)CCCC1
Reactant: O=CO
Solvent: O
Product: N#CC1(NC=O)CCCC1
Reaction time: 3 h

Procedure:
11.0 g (0.1 mol) of 1-amino-1-cyanocyclopentane and 10 ml of 85% formic acid were placed in an apparatus equipped with water-separatory distillation head and boiled for 3 hours. The reaction mixture was then evaporated to constant weight in vacuo.
Reaction SMILES: [Cl-:1].[Cl-].C([N:10]1[CH2:14][CH2:13][C:12]([CH2:16][NH:17][CH:18]2[CH2:20][CH2:19]2)([OH:15])[CH2:11]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[CH:18]1([NH:17][CH2:16][C:12]2([OH:15])[CH2:13][CH2:14][NH:10][CH2:11]2)[CH2:20][CH2:19]1
Reactant: [Cl-]
Reactant: OC1(CNC2CC2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: Cl
Product: OC1(CNC2CC2)CCNC1

Procedure:
7.9 g (24.7 mmol) of 1-benzyl-3-cyclopropylaminomethyl-3-hydroxypyrrolidine dichloride in 100 ml of methanol are hydrogenated on 2 g of palladium/active carbon (10%) at 50° C. and 100 bar. The product is filtered off with suction and concentrated, and the residue is triturated with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.
Reaction SMILES: [C:1]([NH:4][C@@:5]1([C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH2:10][CH:11]=[CH2:12])(=[O:3])[CH3:2].C(Cl)Cl.[CH3:23][C:24]1([CH3:31])[C:28]([CH3:30])([CH3:29])[O:27][BH:26][O:25]1>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([NH:4][C@@:5]1([C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH2:10][CH2:11][CH2:12][B:26]1[O:27][C:28]([CH3:30])([CH3:29])[C:24]([CH3:31])([CH3:23])[O:25]1)(=[O:3])[CH3:2]
Reactant: C=CC[C@H]1CCC[C@@]1(NC(C)=O)C(=O)NC(C)(C)C
Reactant: CC1(C)OBOC1(C)C
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CCC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
A stirred solution of (1S,2R)-1-acetamido-2-allyl-N-tert-butylcyclopentanecarboxamide (0.599 g, 2.25 mmol) in an anhydrous methylene chloride (9 mL) under nitrogen was treated with Ir2Cl2(COD)2 (45 mg, 0.07 mmol) and DiPhos (54 mg, 0.136 mmol) and stirred at room temperature for 30 min. 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.65 mL, 4.48 mmol) was added dropwise and the solution stirred at room temperature for 20 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (40 mL, then 2×15 mL), and the combined organic solution was washed with saturate aqueous sodium chloride (30 mL), dried over MgSO4, and concentrated. The residue was dissolved in minimal dichloromethane and purified by flash column chromatography (silica gel, 40-50% ethyl acetate in heptane) to afford (1S,2S)-1-acetamido-N-tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl) cyclopentanecarboxamide (0.695 g, 78%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 6.72 (br s, NH, 1 H), 5.68 (br s, NH, 1 H), 2.46-2.29 (m, 2 H), 2.10-2.19 (m, 1 H), 2.02 (s, 3 H), 2.00-1.88 (m, 1 H), 1.75-1.60 (m, 3 H), 1.52-1.38 (4 H), 1.32 (s, 9 H), 1.31 (s, 12 H), 0.81-0.70 (m, 2 H); MS (+CI): m/z for C21H39BN2O4: expected 394.3; found 395.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1O)[C:5]([OH:7])=[O:6].CC(C)[O-:14].[Ti+4:16].CC(C)[O-:19].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([O-:1])[C:3]=1[O-:14])([OH:7])=[O:6].[Ti+4:16].[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([O-:1])[C:3]=1[O-:19])([OH:7])=[O:6]
Reactant: CC(C)[O-]
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: [Ti+4]
Solvent: Cc1ccccc1
Product: O=C(O)c1cccc([O-])c1[O-]
Temperature: 100 °C

Procedure:
A solution of 3,4-dihydroxybenzoic acid (30.8 g, 200 mmol) and toluene (220 ml) was dehydrated by distilling 20 mL of the solution. Thereafter, 28.4 g (100 mmol) of titanium(IV) isopropoxide (TTIP) was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (3,4-dihydroxybenzoic acid-titanium complex) was brown in color. The yield amount was 35.0 g (99.4 mmol), and the yield percentage was 99%. 3.52 g of 3,4-dihydroxybenzoic acid-titanium complex was dissolved into 100 mL of 1:4 acetylacetone/ethyl acetate to produce a coating liquid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.NC(O)CC>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: CCC(N)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 182.5 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (7.9 ml) is added to the bottle, and DL-aminopropanol (7.0 ml) is added thereto under the temperature. The above mixture is reacted under the temperature for 1 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amounts of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (11.6 g). The yield is about 70.4%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=4)[CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C1(OC)C=CC=CC=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>ClCCl>[F:47][C:46]([F:49])([F:48])[C:44]([OH:50])=[O:45].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([S:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=4)[CH:26]=3)(=[O:24])=[O:23])[CH2:20][CH2:21]2)=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCNCC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a stirring solution of 1-(1-Boc-piperidin-4-yl-carbonyl)-4-(6-chloronaphthalen-2-ylsulfonyl)piperazine (2.2 g, 4.2 mmol) in dichloromethane (25 mL) was added anisole (2 mL) followed by TFA (25 mL). After 90 min, the solvents were removed in vacuo and the residue was dissolved in a few mL of dichloromethane and diluted with diethyl ether (200 mL). After stirring for 2 h, the suspension was sonicated and filtered and then the solid was washed with diethyl ether and dried in vacuo to give 2.25 g (99%) of a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.B(O[O-])=[O:12].[Na+].[B-]1(O)(O)OO[B-](O)(O)OO1>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-:12]
Reactant: O=BO[O-]
Reactant: c1ccc2cnccc2c1
Agent: O[B-]1(O)OO[B-](O)(O)OO1
Agent: [Na+]
Solvent: CC(=O)O
Product: [O-][n+]1ccc2ccccc2c1
Reaction time: 8 h
Yield: 109 %

Procedure:
To a solution of isoquinoline (76.93 g, 595.6 mmol) in acetic acid (520 mL) was added portionwise every 10 min. 33.6 g of sodium perborate, NaBO3.4H2O. Over a 1 hour period a total of 201.6 g (1.31 mole) of perborate was added. The resulting mixture was stirred at 60° C. for 24 hours after which acetic acid was removed by passing a stream of air over the surface of the liquid contained in a large flat vessel overnight. The remaining solid was dissolved in 1 L of water and the solution neutralized with solid sodium bicarbonate. The solution was extracted with chloroform (3×300 mL) and the organic extracts dried over magnesium sulfate. Chloroform was evaporated and the residual white solid was redissolved in chloroform and precipitated by addition of hexane to give 65 g (75%) of the N-oxide: mp 138-140° C. (lit mp 141-142° C.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:24]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:26][OH:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:24]=1
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Br)cc2[nH]1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Stir, at room temperature under argon, a mixture of 1.13 g of 4-(6-bromo-1H-benzimidazol-2-yl)-9H-fluoren-9-one, 0.628 g of hydroxylamine hydrochloride and 1.24 g of sodium acetate in 50 ml of ethanol. The following day, evaporate the reaction medium to dryness under vacuum, take the residue up with 100 ml of water, filter off the solid, and then wash it with 100 ml of water. After drying at 40° C. under vacuum, we obtain 1.17 g of 4-(6-bromo-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z, E), with the following characteristics:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
N-tert-Butyl-3-{4-[4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example E.59) (0.17 g, 0.42 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.14 g, 0.54 mmol) according to the general procedure VI. Obtained as an off-white solid (0.22 g), which was subsequently deprotected.
Reaction SMILES: [F:1][C:2]([C:5]1[S:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:6]=1[CH2:18][OH:19])([F:4])[CH3:3].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl>[CH3:20][S:21]([O:19][CH2:18][C:6]1[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[N:8][S:9][C:5]=1[C:2]([F:4])([F:1])[CH3:3])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(-c2nsc(C(C)(F)F)c2CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(-c2nsc(C(C)(F)F)c2COS(C)(=O)=O)cc1
Temperature: 28 °C
Reaction time: 0.5 h

Procedure:
Into a 25-mL round-bottom flask, was placed [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methanol (32 mg, 0.11 mmol, 1.00 equiv), dichloromethane (2 mL), MsCl (0.0258 g), triethylamine (34.2 mg, 0.34 mmol, 2.99 equiv). The resulting solution was stirred for 0.5 h at 28° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water, the organic phase was collected. The aqueous phase was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.061 g (crude) of [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methyl methanesulfonate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C15H17F2NO3S2, 362.4 (M+H). found 362.4.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][C:48]([CH3:54])([CH3:53])[CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[CH3:47][C:48]([CH3:54])([CH3:53])[CH2:49][C:50]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:51]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added 3,3-dimethylbutanoyl chloride (0.050 g, 0.372 mmol) followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 3 hours. The reaction mixture was partitioned between water and ethyl acetate. The residue was not purified (yield not calculated). ES-MS (m/z) 701 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:24])[NH:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:24])[NH:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCCOc1ccccc1-c1nc2cc([N+](=O)[O-])ccc2c(=O)[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCOc1ccccc1-c1nc2cc(N)ccc2c(=O)[nH]1

Procedure:
A stirred solution of 7-nitro-2-(2-propoxyphenyl)-4(3H)-quinazolinone (3.0 g) in dry methanol (450 ml) was treated sequentially under a carbon dioxide atmosphere with 5% Pd/C (1.5 g) and anhydrous ammonium formate (2.8 g). After 60 minutes solids were removed by filtration and the filtrate evaporated to dryness. The residue was partitioned between water and dichloromethane, the organic layer separated, dried (magnesium sulphate) and evaporated. The residue was recrystallised from diethyl ether-petroleum ether to give 7-amino-2-(2-propoxyphenyl)-4(3H)-quinazolinone, 2.7 g, m.p. 185° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]([CH3:35])[CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]([CH3:35])[CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(C(=O)c2cnc3c(C(=O)O)cnn3c2NCc2ccccc2)CCC1c1ccccc1
Reactant: CS(N)(=O)=O
Product: CC1CN(C(=O)c2cnc3c(C(=O)NS(C)(=O)=O)cnn3c2NCc2ccccc2)CCC1c1ccccc1
Yield: 17.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(3-methyl-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.209 g, 0.445 mmol) obtained in step 6 and methanesulfonamide (0.211 g, 2.23 mmol), the title compound (0.042 g, 17%) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5]1.[C:17]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].ClCCl>C(#N)C.O>[C:17]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][N:4]3[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:5]3)[CH2:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=c1ccc(-c2ccccc2)nn1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: O=c1ccc(-c2ccccc2)nn1CCN1CCN(c2cccc3ccccc23)CC1
Yield: 68.2 %

Procedure:
A mixture of 2-(2-chloroethyl)-6-phenyl-3(2H)-pyridazinone (1.9 g, 7.5 mmol), 1-naphthylpiperazine (1.7 g, 8 mmol), K2CO3 (1.12 g, 8 mmol) and KI (10 mg) in acetonitrile (50 mL) was refluxed for 7 hours. When heating, was over, the solvent was eliminated at reduced pressure and distributed between dichloromethane and water; the aqueous phase was extracted with dichloromethane (twice). The organic extracts were collected, dried over anhydrous Na2SO4 and concentrated to dryness. The obtained residue was purified by flash chromatography (CH2Cl2/MeOH 97:3) yielding 2-[2-(4-naphthylpiperazine-1-yl)-ethyl]-6-phenyl-3(2H)-pyridazinone (2.1 g). The product was dissolved in ethanol and by adding hydrochloric acid concentrated up to pH=1 yielded a white solid, which was re-crystallised in methanol, yielding the hydrochloride of the title compound, presenting a M.P. higher than 260° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1>>[F:15][C@H:14]1[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]([NH:1][CH:22]2[CH2:23][CH2:24][O:19][CH2:20][CH2:21]2)[CH:3]=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Reactant: O=C1CCOCC1
Product: C[C@]1(c2cc(NC3CCOCC3)ccc2F)N=C(N)COC[C@@H]1F
Yield: 38.3 %

Procedure:
In an analogous manner as described for example 1 the reductive amination of (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (intermediate A10B) (20 mg, 78.4 μmol) and dihydro-2H-pyran-4(3H)-one (CAS [29943-42-8]) (8.63 mg, 7.96 μl, 86.2 μmol) yielded the title compound (10.2 mg, 38.4%) as a colorless oil. MS (ISP): m/z=340.2 [M+H]+.