Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.O.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(Nc2ccccc2Cl)n1
Temperature: 20 °C
Yield: 97.6 %

Procedure:
272.0 g of cyanuric chloride (content >99%), 1,000 ml of water and 275 ml of toluene are mixed at 5° C. The aqueous phase thereby assumes a pH value of 3.5. 188.2 g of o-chloroaniline are added in the course of 30 minutes without cooling or heating the mixture, whereupon the temperature rises to 30° C. A pH value of 7 is then established in the course of 1 hour by addition of 45% strength sodium hydroxide solution, whereupon the temperature rises up to 55° C. The mixture is then cooled to 20° C. in the course of 15 minutes. The product is filtered off, washed salt-free with water and dried at 60° C. in a waterpump vacuum. 396.5 g of 2-(2-chlorophenylamino)-4,6-dichloro-s-triazine are obtained with a melting point of 159° C. and a content of 98.9%, which corresponds to a yield of 97.5% (based on 99 % pure cyanuric chloride).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](O)=O>>[Br:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(F)c(Br)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(F)c(Br)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-bromo-4-fluorobenzoic acid: MS (ESI): m/z 465 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.[CH3:19][C:20]([S:23]([NH2:26])(=O)=[O:24])([CH3:22])[CH3:21]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[N:26][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a solution of 6-bromo-2-phenylchroman-4-one (2.010 g, 6.63 mmol) and 2-methyl-2-propane sulfonamide (804 mg, 6.63 mmol) in anhydrous THF (22 mL) is added Ti(OEt)4 (3.025 g, 2.80 mL, 13.22 mmol). The resulting mixture is heated to reflux for 20 h. Brine (10 mL) is added after the mixture is cooled to rt, and stirred vigorously for 10 min. The mixture is filtered through a pad of Celite, and washed with ethyl acetate (50 mL). The filtrate is washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue is purified through chromatography on silica gel to afford N-(6-bromo-2-phenylchroman-4-ylidene)-2-methylpropane-2-sulfinamide 1.05 g, 39%) as a light yellow solid. MS ESI +ve m/z 406 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[S:19][C:20]([S:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=O)[C:25]=3[F:33])=[CH:21][N:22]=2)=[N:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:34][CH2:35][C:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([OH:40])[CH2:37][CH2:38][CH3:39].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[F:33][C:25]1[C:26]([C:30](=[O:32])[NH:34][CH2:35][C:36]([OH:40])([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:38][CH3:39])=[N:27][CH:28]=[CH:29][C:24]=1[S:23][C:20]1[S:19][C:18]([NH:17][C:14]2[N:15]=[CH:16][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:12][CH:13]=2)=[N:22][CH:21]=1
Reactant: CN(Cc1ccc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)nc1)C(=O)OC(C)(C)C
Reactant: CCCC(O)(CN)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccc(CN(C)C(=O)OC(C)(C)C)cn3)s2)c1F)c1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of 4-(2-(5-((tert-butoxycarbonyl(methyl)amino)methyl)pyridin-2-ylamino)thiazol-5-ylthio)-3-fluoropicolinic acid (120 mg, 0.244 mmol) and 1-amino-2-phenylpentan-2-ol (1.3 eq, 0.317 mmol, 57 mg) in NMP (4 mL) was added HOBT (1.3 eq, 0.317 mmol, 43 mg), EDAC (2 eq, 0.488 mmol, 94 mg) and diisopropylethylamine (5 eq, 1.22 mmol, 157 mg, 213 uL). The reaction was stirred at 23° C. overnight. The product was precipitated by addition of water to the reaction mixture. The solid was isolated by filtration to give the crude title material (97 mg, 61%) as a solid which was used as such in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.76 (3H, t, J=7.33 Hz), 0.90 (1H, m), 1.18-1.32 (1H, m), 1.41 (9H, s), 1.65-1.84 (2H, m), 2.75 (3H, s), 3.62 (2H, d, J=5.81 Hz), 4.32 (2H, s) 7.04 (1H, t, J=5.18 Hz), 7.11 (1H, d, J=8.59 Hz), 7.20 (1H, t, J=7.33 Hz), 7.31 (2H, t, J=7.71 Hz), 7.44 (2H, d, J=7.33 Hz), 7.66 (1H, s), 7.82 (1H, s), 8.13-8.32 (3H, m), 11.93 (1H, s). LC/MS (M+H)+: 653. Ret. time: 2.257 (Condition A).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]([C:13](O)=[O:14])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:4]=2[CH:3]=1.C(Cl)(C([Cl:22])=O)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]([C:13]([Cl:22])=[O:14])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:4]=2[CH:3]=1
Reactant: O=C(O)c1sc2ccc(Cl)cc2c1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1sc2ccc(Cl)cc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To compound 18f in CH2Cl2 (5 mL) at room temperature was added (COCl)2, followed by 2 drops of DMF. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 18g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:15].[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].[I-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[C:31]([F:33])([F:32])[F:34])[C:6]=1[CH3:15]
Reactant: COC(=O)Cc1c(C)[nH]c2nc(Cl)ccc12
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2nc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled solution of (6-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (Example 99e) (0.03 g, 0.13 mmol) in DMF (1.0 ml) under an inert atmosphere of Argon is added sodium hydride (0.006 g of a 60% dispersion in mineral oil, 0.14 mmol). The reaction mixture is stirred at 0° C. for 45 minutes and then treated with 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (Example 95a) (0.067 g, 0.21 mmol) followed by sodium iodide (0.031 g, 0.21 mmol). Stirring is continued at 0° C. for 2 hours and then the reaction mixture is poured onto water (15 ml) and extracted with DCM (5 ml). The organic portion is separated and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:4) to yield the product which was further purified by trituration with ethyl acetate/iso-hexane to afford the titled product. (MH+475).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][N:18]2[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=[C:17]2[CH:16]=1)(C)(C)C>C(Cl)Cl>[C:24]1([C:22]2[N:23]=[C:17]3[CH:16]=[C:15]([NH2:14])[CH:20]=[CH:19][N:18]3[CH:21]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Trifluoroacetic acid (30 ml) was added to a solution of (2-phenyl-imidazo[1,2-a]pyridin-7-yl)-carbamic acid tert-butyl ester (4.81 g, 15 mmol) in CH2Cl2 (30 ml), and the mixture was stirred at r.t. overnight. The mixture was then washed (water, 2×50 ml), dried (Na2SO4), and the solvent was evaporated. The title compound (2.25 g, 73%) was obtained from the residue by column chromatography (silica gel, CH2Cl2: MeOH=100:0-60:40). MS (m/e)=210.1 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C(N(CC)CC)C>C1COCC1>[CH2:13]([N:16]([CH2:17][CH2:18][CH3:19])[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1)[CH2:14][CH3:15]
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: CCCNCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)c1nc(C)cc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 82.7 %

Procedure:
A mixture of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (0.411 g, 2.20 mmol), di-n-propylamine (0.668 g, 6.60 mmol), triethylamine (0.267 g, 2.64 mmol), and THF (5 ml) was stirred at room temperature for 55 min and then at reflux for 1.3 h, at which time is was cooled and partitioned between ethyl acetate and a mixture of brine and aq. sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated and then chromatographed on silica gel using ethyl acetate-hexane (90/10) to give methyl 2-(dipropylamino)-6-methylpyrimidine-4-carboxylate (0.457 g) as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[F:26][C:27]([F:33])([F:32])[S:28]([NH2:31])(=[O:30])=[O:29]>>[F:26][C:27]([F:33])([F:32])[S:28]([NH:31][C:17]([C:14]1[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:21][CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:9][CH3:10])=[CH:12][CH:13]=1)=[O:18])(=[O:30])=[O:29]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(=O)O)nn1
Product: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(=O)NS(=O)(=O)C(F)(F)F)nn1

Procedure:
The title compound was prepared from 6-[N-(5-chloro-2-(2-methylprop-2-en-1-yloxy)-benzyl)-N-ethylamino]pyridazin-3-carboxylic acid (example 19) and trifluoromethanesulphonamide using a similar method to that of example 11 (18%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1>[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[CH2:12][C@@H:9]1[CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(Cc2nc3ccccc3[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1
Temperature: 65 °C

Procedure:
The cis/trans mixture of 4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid ethyl esters (D) (600 mg, 2.1 mmol) was dissolved in a minimal amount of THF (5 mL) and mixed with concentrated aqueous LiOH (2 mL). The reaction was stirred vigorously and heated at 65° C. for 3 h. After cooling and concentration, the crude material was dissolved in 1:1 water/CH3CN and subjected to preparative reverse-phase HPLC to yield (E) cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (200 mg, 37%): 1H NMR (400 MHz, CD3OD) δ 7.77 (m, 2 H), 7.60 (m, 2H), 3.11 (d, 2H), 2.62 (m, 1H), 2.10 (m, 3H), 1.65 (m, 4H), 1.43 (m, 2H); mass spectrum m/z 259 [(M+H)+; calcd for C15H19N2O2: 259].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([CH2:11][C:12]([O:14]C)=O)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:16]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([CH2:11][C:12]([NH2:16])=[O:14])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)CS(=O)(=O)c1cncc(Br)c1
Reactant: N
Solvent: CO
Product: NC(=O)CS(=O)(=O)c1cncc(Br)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(5-bromopyridin-3-ylsulfonyl)acetate (0.2 g, 0.67 mmol) was added 5% ammonia in methanol (10 mL). Upon completion of addition, the reaction mixture was stirred at 60° C. for 4 h. After this time, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was concentrated under reduced pressure to afford 2-(5-bromopyridin-3-ylsulfonyl)acetamide (0.2 g) as a white solid. LCMS Method W: retention time 0.92 min; [M−1]=277.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:17])[O:5][C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[Cl:18]N1C(=O)CCC1=O>ClCCl>[Cl:18][CH2:1][C:2]1[N:3]=[C:4]([NH2:17])[O:5][C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1nc(N)oc1-c1cccc2ccccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Nc1nc(CCl)c(-c2cccc3ccccc23)o1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A solution of 4-methyl-5-naphthalen-1-yl-oxazol-2-ylamine (3, 800 mg), N-chlorosuccinimide (480 mg) and dichloromethane (30 mL) were irradiated with a 150W (tungsten/halogen) lamp at reflux for 8 hours. After cooling to room temperature, the solution was diluted with dichloromethane (50 mL) and washed with a saturated solution of sodium hydrogen carbonate (50 mL), water (50 mL) and brine (50 mL). The solvent was removed under reduced pressure and the resultant residue was purified by column chromatography affording 4-chloromethyl-5-naphthalen-1-yl-oxazol-2-ylamine (27) (411 mg, 45%) as an orange foam, 1H NMR (DMSO-D6): 4.45 (2H, s), 6.95 (2H, br s), 7.5-7.6 (4H, m), 7.95-8.00 (3H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:30])=[CH:24][CH:23]=1
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(Cl)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH2:1]([C:8]([CH2:19][CH2:20][C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])(C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[Cl-].[Li+].O>CS(C)=O>[F:32][C:21]([F:33])([C:22]([F:30])([F:31])[C:23]([F:28])([F:29])[C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Yield: 88.5 %

Procedure:
A solution of diethyl 2-(6-heptenyl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)malonate (1.05 g, 2.1 mmol) in dimethyl sulfoxide (10 ml) was stirred with lithium chloride (0.18 g, 4.2 mmol) and water (0.038 ml, 2.1 mmol) for 5 hours at a temperature of 170° C. to 180° C. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40) to give ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate (0.80 g, Yield 89%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[F-:13].[K+]>CN(C)C=O>[F:13][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12]
Reactant: [F-]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(C(F)F)c(C=O)c1F
Temperature: 150 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Under argon 19.4 g (100 mmol) of 5-chloro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde (II-1) were initially charged in dimethylformamide. This was followed by the addition of 8.6 g (150 mmol) of potassium fluoride (KF water content 0.05%), heating to 150° C. and subsequent stirring at that temperature for 8 hours. This was followed by dilution of the mixture with ethyl acetate, filtration and distillative removal of the solvent in vacuo at 0.5 mbar and 70° C. to obtain 16 g (90% of theory) of 5-fluoro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde having a purity of 99% (melting point 68° C.).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])C.[OH-:27].[Na+].OO.Cl>O.C1COCC1>[OH:27][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:26]
Reactant: C=CCCCCCCCCCCCCCCCCCCCC(=O)OCC
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCCCCCCCCCCCO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
22-Hydroxy-docosanoic acid was synthesized according to Mori et al., Liebigs Ann. Chem., (1991), 253-257. Briefly, under N2 atmosphere 6.6 g Docos-21-enoic acid ethyl ester and 30 ml THF were combined and cooled down to 0° C. Then 0.5 eq. (9 ml) borane/THF complex was added dropwise and the mixture was allowed to stir for 2 hours at room temperature. After the addition of 1.2 ml H2O the suspension was again cooled down to 0° C. and 15 ml 3M NaOH and 2 ml 35% H2O2 were added. The mixture was stirred for one hour at 50° C. Then the temperature was brought to room temperature and the pH was adjusted to pH 2-3 with 2N HCl. The solid was fritted, washed with H2O, codistilled three times with CHCl3 and recrystallized from CHCl3. After a further treatment with NaOH (3M in H2O) in THF at 50° C. over 1.5 days the pH was again adjusted to pH 2-3 and the crude product was fritted, washed with H2O and codistilled two times with CHCl3. The product was characterized by thin layer chromatography and 1H-NMR.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:9]([CH2:12]Br)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[S:16]([O-:19])([O-:18])=[O:17].[Na+:20].[Na+]>C(O)C.O>[Na+:20].[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][S:16]([O-:19])(=[O:18])=[O:17])=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(CS(=O)(=O)[O-])ccc(Br)c1OC
Yield: 100.1 %

Procedure:
A mixture of methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89, 1.0 g) and sodium sulphite (0.445 g) in ethanol (1 ml) and water (10 ml) was stirred and heated at reflux for 2 hours. After cooling, the mixture was evaporated to dryness to give (4-bromo-3-methoxy-2-methoxycarbonylphenyl)-methanesulphonic acid sodium salt (1.07 g) as a white solid which was used without further characterization.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.[H-].[Na+].I[CH3:20].O>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1
Reactant: CI
Reactant: CCOC(=O)Cc1ccc(OCOC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc(OCOC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(4-(methoxymethoxy)phenyl)acetate (1.75 g, 7.80 mmol) in DMF (50 mL) was slowly added sodium hydride (330 mg, 8.25 mmol) and iodomethane (1.13 g, 7.96 mmol) at 0° C. The reaction mixture was stirred for 1 hour at 0° C. The mixture was added water (50 mL) and extracted with EtOAc. The organic layer was dried with MgSO4. The organic layer was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=15/1.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH2:31])[CH2:29][OH:30].CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH:31][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:29][OH:30]
Reactant: NC(CO)c1ccc(F)cc1F
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC(CO)c2ccc(F)cc2F)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(2,4-difluoro-phenyl)-2-hydroxy-ethylamine and DIEA to give 2-[1-(2,4-difluoro-phenyl)-2-hydroxy-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 455 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)#[N:2].[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>>[C:1]([C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1ccccc1Oc1ccc(NCc2cccnc2)cc1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(Oc2ccccc2C#N)cc1

Procedure:
Using the method of Example 342 using N-(4-(2-cyanophenoxy)phenyl)pyridin-3-ylmethylamine and ethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 98:2 to 96:4 DCM/MeOH. Anal Calcd for C21H19N3O3S.0.2H2O: C, 63.52; H, 4.92; N, 10.58. Found: C, 63.51; H, 4.79; N, 10.55. MS found 394.0 [M+H]+
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[O:8][N:7]=1)([CH3:5])[CH3:4])#[N:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[S:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39]>C1COCC1>[C:1]([C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([NH:39][C:38]2[CH:40]=[CH:41][CH:42]=[C:36]([S:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][N:27]=3)[CH:37]=2)=[O:20])[O:8][N:7]=1)([CH3:4])[CH3:5])#[N:2]
Reactant: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C#N)no4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 32 %

Procedure:
A mixture of phenyl 3-(2-cyanopropan-2-yl)isoxazol-5-ylcarbamate (prepared as described in Example 125A steps 1 through 3) (95 mg, 0.35 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (100 mg, 0.319 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was separated and dried over magnesium sulfate. Concentration under reduced pressure gave a solid which was triturated with methanol to afford 1-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (50 mg, 32%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.52 (brs, 1H), 9.14 (brs, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.57 (m, 1H), 7.46 (m, 1H), 7.30-7.36 (m, 3H), 6.28 (s, 1H), 3.99 (s, 6H), 1.68 (s, 6H); LC-MS (ESI) m/z 491 (M+H)+.