Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([S:11][CH3:12])[C:5]([C:6](O)=[O:7])=[C:4]([F:13])[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([S:11][CH3:12])[C:5]([CH2:6][OH:7])=[C:4]([F:13])[CH:3]=1
Reactant: CSc1cc(Br)cc(F)c1C(=O)O
Solvent: C1CCOC1
Product: CSc1cc(Br)cc(F)c1CO
Temperature: 62.5 °C
Yield: 90 %

Procedure:
To a 20 L flask was charged 4-bromo-2-fluoro-6-(methylthio)benzoic acid (1400 g, 1.0 eq) followed by THF (14 L, 10 vol) under nitrogen. To this solution was added borane-dimethyl sulfide complex (802.41 g, 1000 mL) at 25-28° C. over a period of 30-45 min. The reaction temperature was raised to 60-65° C. over a period of 30-45 min and the temperature maintained until HPLC showed <1% of 4-bromo-2-fluoro-6-(methylthio)benzoic acid (˜3-4 h). On completion of the reaction the mixture was cooled to 10-15° C. over a period of 30-40 min. The reaction was then quenched with methanol (2.1 L, 1.5 vol) over a period of 1 to 1½ h at 10-15° C. The reaction mass was then concentrated under vacuum at 40-50° C./0.4 to 0.7 mbar to 1 to 1.5 volumes. The resultant mixture was dissolved in DCM (8.4 L, 6 vol). The organic layer was washed with an ammonium chloride solution (560 g NH4Cl in 2.8 L water, 2 vol). The phases were separated and the organic layer was washed with 10% NaHCO3 solution (2.8 L, 2 vol), saturated brine solution (2.1 L, 1.5 vol) and water (4.2 L, 3 vol). The organic layer was separated and dried over sodium sulfate (700 g). The sodium sulfate was removed by filtration and washed with DCM (2.8 L, 2 vol). The organic layer was concentrated under vacuum at 40-45° C./0.4 to 0.7 mbar to 1 to 1.2 vol to afford the product which was dried under vacuum at 45-50° C./0.4 to 0.7 mbar. The title product was obtained in 90% yield (1200 g) with 90.07 Area %.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:7]2[C:14]([O:15]C)=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:7]2[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cccc(OC)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1csc2cccc(O)c12
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of (4-Methoxy-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (0.7 g, 2.8 mmol) in methylene chloride (18 mL) is added BBr3 (1.0 M, heptane, 8.6 mL, 8.6 mmol) at −20˜−30° C. The reaction mixture is allowed to warm to room temperature over 2 hrs, and TLC indicated clean conversion. The reaction is quenched by ice water, extracted with methylene chloride, dried over sodium sulfate, concentrated. Column chromatography on silica gel eluted with hexanes/ethyl acetate yields the title compound (0.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1.Br[CH2:21][CH2:22][F:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][CH2:21][CH2:22][F:23])=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1
Reactant: Cc1ccc(Br)cc1Cc1cc2cc(O)ccc2s1
Reactant: FCCBr
Product: Cc1ccc(Br)cc1Cc1cc2cc(OCCF)ccc2s1

Procedure:
5-Bromo-1-(5-methoxybenzo[b]thiophene-2-yl methyl)-2-methylbenzene obtained in Reference Example 158 was treated in a manner similar to Reference Example 132-(1) to give 5-bromo-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene as colorless powder. ESI-Mass m/Z 331/333 (M−H). (2) The above 5-bromo-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene and 1-bromo-2-fluoroethane were treated in a manner similar to Reference Example 132-(2) to give the desired 5-bromo-1-(5-(2-fluoroethyloxy)benzo[b]thiophene-2-ylmethyl)-2-methylbenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH:37](=O)[CH3:38]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@H:23]5[CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: CC=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@H]1CCNC[C@H]1F
Product: CCN1CC[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis)-1-ethyl-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 201) and acetaldehyde (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][N:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:33]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])#[N:34].C(O)(=O)C.N1CCCCC1>C(O)C>[C:33]([C:35](=[CH:21][C:20]1[CH:19]=[N:18][C:17]([NH:16][C:13]2[N:14]=[C:15]3[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3=[N:11][CH:12]=2)=[CH:24][CH:23]=1)[C:36]([N:38]([CH3:40])[CH3:39])=[O:37])#[N:34]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cn3)nc12
Reactant: CN(C)C(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)nc1
Yield: 88.8 %

Procedure:
To a 50 ml three necked round bottom flask 6-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)-nicotinaldehyde (0.33 g, 0.00072 mole) and 2-cyano-N,N-dimethylacetamide (0.245 g, 0.00218 mole) was taken in ethanol (10 ml). To this reaction mixture, piperidine acetate (3.3 M solution in water) (0.1 ml) was added drop wise at RT. After completion of the addition, reaction mixture was refluxed for 4 hrs. After completion of the reaction, the ethanol was distilled out and water was added to residue. The aqueous layer was extracted with ethyl acetate and organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified by triturated with n-pentane (10.0 ml), pentane layer was decanted and solid was dried under vacuum to yield 0.35 g of 2-cyano-N,N-dimethyl-3-(6-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)pyridin-3-yl)acrylamide.
Reaction SMILES: [Mg].Br[CH2:3][CH:4]([CH2:7][CH3:8])[CH2:5][CH3:6].[CH3:9][C:10](=[CH:13][CH2:14][CH3:15])[CH:11]=[O:12]>CCOCC>[CH3:9][C:10]([CH:11]([OH:12])[CH2:3][CH:4]([CH2:7][CH3:8])[CH2:5][CH3:6])=[CH:13][CH2:14][CH3:15]
Reactant: CCC(CC)CBr
Reactant: CCC=C(C)C=O
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)CC(CC)CC

Procedure:
A Grignard reagent, prepared by reacting 11.4 g (0.47 g atom) of magnesium in 100 ml of ether and 77.6 g (0.47 mol) of 1-bromo-2-ethylbutane in 400 ml of ether, is reacted with 38.4 g (0.39 mol) of 2-methyl-2-pentenal in a manner analogous to Example 5. Fractional distillation of the crude product (79.8 g) over a 15 cm Widmer column gives 29.9 g (40.3%) of olfactorily good 4-methyl-7-ethyl-3-nonen-5-ol of boiling point 105°-106° C./12 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:5]=1[S:16]([NH2:19])(=[O:18])=[O:17])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([F:14])([F:13])[F:15])[C:5]=1[S:16]([NH2:19])(=[O:18])=[O:17]
Reactant: NS(=O)(=O)c1c(OCC(F)(F)F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(OCC(F)(F)F)c1S(N)(=O)=O
Reaction time: 0.5 h

Procedure:
30 mg of 10% Pd on carbon are added to a solution of 2-nitro-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide (63 mg, 0.21 mmol) in EtOH (10 mL). The mixture is stirred for 30 min under hydrogen. The catalyst is removed by filtration. Evaporation of solvent gives 2-amino-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](N1CCCC1)=[CH:13]2>O>[CH3:6][O:7][C:8]1[C:9]2[CH2:10][CH2:11][C:12]3[NH:5][C:1](=[O:4])[CH2:2][CH2:3][C:13]=3[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc2c1CCC(N1CCCC1)=C2
Reactant: C=CC(N)=O
Solvent: O
Product: COc1cccc2c1CCC1=C2CCC(=O)N1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 23 %

Procedure:
A mixture of acrylamide (146 g, 2.0 mol) and 1-(5-methoxy-3,4-dihydronaphthalen-2-yl)pyrrolidine (156 g, 0.68 mol) was heated at 80° C. for 2 h and then 130° C. for a further 0.75 h. The mixture was cooled and water (1L) was added. The resultant brown precipitate was collected by filtration, washed with water and dried in vacuo. Trituration with hot ethanol (2L) gave the title compound as a white solid (35.9 g, 23%).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[N:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9].Cl.CNC.P(C#N)(OCC)(OCC)=O>CN(C)C=O.O>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[N:30]=[C:29]([C:31]([N:3]([CH3:4])[CH3:1])=[O:32])[CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C(=O)O)n3)cs2)cc1OCC
Reactant: CCN(CC)CC
Agent: CCOP(=O)(C#N)OCC
Agent: CNC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3cccc(C(=O)N(C)C)n3)cs2)cc1OCC
Reaction time: 3 h

Procedure:
1.13 ml of triethylamine was dropwise added, at room temperature, to a solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(2-carboxy-6-pyridyl)thiazole, 245 mg of dimethylamine hydrochloride and 515 mg of diethyl cyanophosphate in 15 ml of dimethylformamide. The mixture was stirred at the same temperature for 3 hours. The reaction mixture was mixed with 20 ml of water. The resulting mixture was extracted with 50 ml of dichloromethane three times. The dichloromethane layer was dried over sodium sulfate and concentrated. The residue was recrystallized from n-hexane-ethyl acetate-dichloromethane to obtain 800 mg of 2-(3,4-diethoxyphenyl)-4-(2-dimethylaminocarbonyl-6-pyridyl)thiazole.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:13][C:10]2[CH:11]=[CH:12][C:5]3[CH2:4][CH2:3][C:2]([F:14])([F:1])[CH2:8][CH2:7][C:6]=3[CH:9]=2)=[N:17][CH:18]=1
Reactant: Nc1ccc2c(c1)CCC(F)(F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(F)(F)CC3)ncc1Cl
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
Into a microwave vial was placed 7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (79 mg, 0.00040 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.0003 mol) in isopropyl alcohol (4 mL, 0.05 mol). 4N HCl-dioxane (0.04 g, 0.0003 mol;) was added to the reaction mixture and the contents subjected to microwaves at 120° C. for 10 min. The reaction mixture was resubjected to the same microwave conditions for an additional 10 min. A solid had precipitated out of the reaction mixture, was collected by filtration then redissolved in methylene chloride (6 mL) and washed with sat. aqueous sodium bicarbonate (1×5 mL) and water (2×5 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-[5-Chloro-2-(7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a brown solid (38 mg, 29%). MP: 160-168° C.; 1HNMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.46 (s, 1H), 8.80 (d, 1H, J=4.5 Hz), 8.74 (d, 1H, J=7.6), 8.26 (s, 1H), 7.79 (d, 1H, J=7.8 Hz), 7.61 (s, 1H), 7.53 (t, 1H, J=7.6), 7.45 (d, 1H, J=7.8), 7.2 (t, 1H, J=7.3), 2.85 (d, 3H, J=4 Hz), 2.69-2.77 (m, 4H), 2.06 (m, 4H); MS (m/e) 458 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].CC(C)([O-])C.[Li+].Cl[CH2:28][C:29]([N:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40])[CH3:32])=[O:30]>CN(C=O)C>[Cl:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:31]([CH3:32])[C:29](=[O:30])[CH2:28][N:16]1[C:15]2[CH:14]=[CH:13][C:12]([Cl:20])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[C:19]=2[N:18]=[N:17]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reactant: CN(Cc1ccccc1Cl)C(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1Cl)C(=O)Cn1nnc2c(Oc3cc(Cl)cc(C#N)c3)c(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (25 mg, 0.082 mmol) and lithium tert-butoxide (6.9 mg, 0.089 mmol) were dissolved in DMF (0.5 mL) and allowed to stir for 5 minutes. After this time, the reaction was cooled to 0° C. and 2-chloro-N-(2-chlorobenzyl)-N-methylacetamide as a solution in DMF (0.5 mL) was added dropwise. This was allowed to warm to room temperature and after 16 hours, the reaction was quenched with TFA, diluted with MeCN and purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions were lyophilized to yield the title compound. 1H NMR (DMSO-d6) δ 7.84 (m, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.58 (m, 1H), 7.51 (m, 1H), 7.47 (m, 1H), 7.35 (m, 3H), 6.05 (s, 2H), 4.62 (s, 2H), 3.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:14]([F:17])([F:16])[F:15])([OH:13])CO)[CH:7]=1.I([O-])(=O)(=O)=O.[Na+]>CO.CCOCC>[F:17][C:14]([F:15])([F:16])[C:10](=[O:13])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reaction time: 4 h
Yield: 87.6 %

Procedure:
To a solution of 4.9 g (15.8 mmol) of the above 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol in 100 mL of MeOH was added 10 g (45.9 mmol) of sodium periodate. The mixture was stirred for 4 hours and was then diluted with 100 mL of ether and 100 mL of hexanes, filtered through diatomaceous earth, and concentrated in vacuo. The crude residue was dissolved in hexanes and passed through a pad of silica gel eluting first with hexanes then with EtOAc-hexanes (2:98, then 4:96) to afford 3.85 g (87%) of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a clear oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=1
Reactant: Nc1nc2cc(C(F)(F)F)ccc2s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cc(C(F)(F)F)ccc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-5-trifluoromethylbenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 5-trifluoromethylbenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:45])[CH2:30][CH2:31][CH2:32][N:33]([S:41]([CH3:44])(=[O:43])=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1>>[CH3:45][N:29]([CH3:28])[CH2:30][CH2:31][CH2:32][N:33]([C:34]1[CH:39]=[CH:38][C:37]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:36][CH:35]=1)[S:41]([CH3:44])(=[O:43])=[O:42]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCCN(c1ccc(N)cc1)S(C)(=O)=O
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCCN(C)C)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(3-dimethylamino-propyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.5 (aluminium oxide, methylene chloride/methanol=30:1) C29H32N4O5S
Reaction SMILES: [C:1]([C:3]1([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#N.C[Mg]Br>C1COCC1>[CH3:1][C:3]1([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(N2CCC(c3ccccc3)CC2)C1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
To a 0° C. solution of tert-butyl 3-cyano-3-(4-phenylpiperidin-1-yl)pyrrolidine-1-carboxylate (1.2 g, 3.38 mmol) in THF (16 mL) was added a solution of methylmagnesium bromide (1.4M in THF, 12.06 mL) dropwise. The mixture was stirred at ambient temperature for about 2.5 h, cooled to about 0° C. and quenched by the dropwise addition of saturated ammonium chloride solution. The organic phase was separated, washed with water (2×75 mL) and brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure to yield tert-butyl 3-methyl-3-(4-phenylpiperidin-1-yl)pyrrolidine-1-carboxylate (1.12 g, 3.25 mmol) as a yellow solid. HPLC (Table 1, Method f) Rt 5.01 min; m/z: (M+H)+ 345.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:32])([C@H:23]([N:25]1[CH:29]=[C:28]([CH2:30][OH:31])[N:27]=[N:26]1)[CH3:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:32])([C@H:23]([N:25]1[CH:29]=[C:28]([CH2:30][O:31][S:34]([CH3:33])(=[O:36])=[O:35])[N:27]=[N:26]1)[CH3:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: C[C@@H](n1cc(CO)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](n1cc(COS(C)(=O)=O)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.26 ml) was added dropwise to a solution of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-hydroxy methyl-1H-1,2,3-triazol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (Compound 56, 0.6 g) and methanesulfonyl chloride (0.14 ml) in dichloromethane (20 ml) under ice-cooling. The mixture was stirred for 30 minutes at room temperature. After addition of dichloromethane (20 ml), the mixture was washed with water (20 ml) and 5% sodium hydrogen carbonate aqueons solution (20 ml). The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to give (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methanesulfonyloxymethyl-1H-1,2,3-triazol-1-yl)-1(1H-1,2,4-triazol-1-yl)-2-butanol as colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH3:31]>CO.O1CCOCC1>[NH2:31][C:2]1[CH:7]=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4ccnc(F)c4)n4ccnc34)cc2)CC1
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccnc(N)c4)n4ccnc34)cc2)CC1
Temperature: 120 °C
Reaction time: 96 h
Yield: 16 %

Procedure:
A solution of [5-(2-fluoro-pyridin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.0272, 0.067 mmol) (from Example 125) in a mixture of aq. NH3 (2.5 mL):1M NH3 in MeOH (2.5 mL) is stirred at 100° C. overnight. Additional aq. NH3 (5 mL) and 0.5M NH3 in dioxane (2 mL) are added and the mixture stirred at 120° C. for 4 days. The mixture is concentrated in vacuo and purified by reverse phase HPLC affording the title compound (4.2 mg, 16%). LCMS: Rt 3.76 min (95%) m/z (APCI) 401 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.49-2.53 (4H, t), 3.12-3.15 (4H, m), 6.18 (2H, br s) 6.76 (1H, s), 6.81 (1H, d), 6.97 (2H, d), 7.51 (1H, s), 7.72 (1H, s), 7.88 (2H, d), 8.04 (1H, s), 8.09 (1H, d), 9.55 (1H, s).
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]([OH:8])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:33][N:34]([C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=[C:41]([CH3:49])[CH:40]=1)[CH2:35][CH2:36][NH:37][CH3:38].C(N(CC)CC)C>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH:1]1(/[CH:4]=[CH:5]/[C:6]([N:37]([CH3:38])[CH2:36][CH2:35][N:34]([CH3:33])[C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[C:41]([CH3:49])[CH:40]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: CNCCN(C)c1cc(C)nc2ccccc12
Reactant: O=C(O)/C=C/C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(N(C)CCN(C)C(=O)/C=C/C2CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(E)-3-Cyclopropylprop-2-enoic acid (22 mg, 0.2 mmol) and HBTU (76 mg, 0.2 mmol) were dissolved in a 1:1 mixture of anhydrous THF and anhydrous DMF (2 ml). After 5 minutes N,N′-dimethyl-N-(2-methyl-4-quinolyl)ethane-1,2-diamine (52 mg, 0.23 mmol) and triethylamine (62 μl, 0.45 mmol) were added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 28.3 mg (0.087 mmol, 43.5%).