Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[F:24])=[CH:11][N:10]([CH3:25])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1.[CH2:26]([OH:30])[CH2:27][C:28]#[CH:29]>O1CCCC1.C(N(CC)CC)C.[Cu]I>[CH2:22]([S:19]([C:17]1[CH:16]=[CH:15][C:14]([F:24])=[C:13]([C:12]2[C:4]3[C:5](=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]#[C:28][CH2:27][CH2:26][OH:30])[CH:3]=3)[N:10]([CH3:25])[CH:11]=2)[CH:18]=1)(=[O:21])=[O:20])[CH3:23]
Reactant: C#CCCO
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c3c(OC)nc(Br)cc23)c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c3c(OC)nc(C#CCCO)cc23)c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
A mixture of Example 126A (300 mg, 0.702 mmol), but-3-yn-1-ol (63.8 μl, 0.843 mmol), Pd(dppf)CH2Cl2 (57.3 mg, 0.070 mmol), and copper(I) iodide (13.4 mg, 0.070 mmol) in tetrahydrofuran (9 mL) and triethylamine (3 mL) was purged with nitrogen and then stirred at 70° C. in a sealed tube for 2.5 hours. The mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified on silica gel column (0-8% MeOH in dichloromethane) to give the title compound (200 mg, 68.4% yield)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[O:11]2)[S:7][CH:8]=1)([O-:3])=[O:2].O.[NH2:21][NH2:22]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:11])[NH:22][N:21]=2)[S:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=Cc2cc([N+](=O)[O-])cs2)c2ccccc21
Reactant: NN
Solvent: O
Product: O=c1[nH]nc(Cc2cc([N+](=O)[O-])cs2)c2ccccc12
Temperature: 90 °C

Procedure:
A suspension of 3-(4-nitro-thiophen-2-ylmethylene)-3H-isobenzofuran-1-one (26) (1.95 g, 5.17 mmol) in hydrazine monohydrate (0.6 mL, 12.0 mmol) was heated to 90° C. for 1 hour and then cooled to room temperature. The mixture was filtered and the filtered cake was washed with water (3×40 mL), hexane (2×40 mL) and dried in vacuo at 50° C. Two peaks in LC-MS analysis, (1.0 g, 61%) and required no further purification; m/z (LC-MS, ESP), RT=4.05 mins (M+H) 289, & RT=3.71 mins (M+H) 289.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][NH:16][CH3:17].C1COCC1>>[CH3:15][N:16]([CH3:17])[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNC
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Solvent: C1CCOC1
Product: CN(C)c1nc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A mixture of 2-chloro-6-(trifluoromethyl)nicotinic acid (APOLLO, 2.5 g, 11.1 mmol) and 2M N-methylmethanamine in THF solvent (50 ml, 25 mmol) was stirred for 24 hours at room temperature according to J. Med. Chem., 2005, 48, 71. Then the reaction mixture was evaporated in vacuo to give the title compound (2.5 g, 96%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=3[CH3:33])[CH2:22][CH2:21]2)=[O:19])=[C:14]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:13]=1>>[CH3:33][C:27]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:26]=1[N:23]1[CH2:22][CH2:21][N:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:5]3[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]3(=[O:10])=[O:9])=[CH:13][C:14]=2[S:34]([CH3:37])(=[O:36])=[O:35])=[O:19])[CH2:25][CH2:24]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(C)[C@H]1CCS(=O)(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@@H](C(C)C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 7.7 %

Procedure:
Using (R)-3-isopropylisothiazolidine 1,1-dioxide (300 mg) described in Preparation Example 8 and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 4, the title compound (41 mg) was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([CH:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:10]1.O>C(#N)C>[Br:1][C:10]1[S:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]=1[CH:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(OC(C)(C)C)c1csc2ccccc12
Solvent: O
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(Br)sc2ccccc12
Reaction time: 20 h
Yield: 44 %

Procedure:
N-bromosuccinimide (67 mg, 0.37 mmol) was added at room temperature to a stirred solution of methyl 2-(1-benzothiophen-3-yl)-2-(tert-butoxy)acetate (4b) (70 mg, 0.25 mmol) in acetonitrile (2 mL) under a nitrogen atmosphere. After 20 hours, water (10 mL) was added and the reaction mixture was extracted with dichloromethane (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (4c) as a pale oil (40 mg, 0.11 mmol, 45%).
Reaction SMILES: [CH2:1]([N:10]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13](C(OC(C)(C)C)=O)[C:12]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])Cl)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(Cl)[Cl:54]>>[CH2:1]([N:10]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][C:18]=2[Cl:54])[NH:13][C:12]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)C1(Cl)C(N(CC(=O)c2ccccc2)Cc2ccccc2)c2ccc(Cl)cc2N1C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N(CC(=O)c1ccccc1)Cc1ccccc1
Reaction time: 4 h
Yield: 59 %

Procedure:
Dissolve 3-[(phenacyl)benzylamino]-2-carbethoxy-2,6-dichloro-1-tert-butyloxycarbonyl-indole (0.68 g, 1.26 mmol) in methylene chloride (5 mL) and add, by dropwise addition, trifluoroacetic acid (5 mL). Stir for 4 hours then slowly add to saturated sodium hydrogen carbonate (100 mL). Extract into methylene chloride, dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) to give the title compound (0.34 g, 59%); mp 174°-5° C.
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][C:19]([Cl:21])=[N:18][CH:17]=3)[C@@H:14]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:38])[CH3:37])[C:28]([O:30]C(C)(C)C)=[O:29])=[O:10])=[CH:7][C:6]=1[O:41][CH3:42])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][C:19]([Cl:21])=[N:18][CH:17]=3)[C@@H:14]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:37])[CH3:38])[C:28]([OH:30])=[O:29])=[O:10])=[CH:7][C:6]=1[O:41][CH3:42])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C(=O)N2[C@@H](c3cnc(Cl)s3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](c3cnc(Cl)s3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][N:25]1[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[NH:27][C:26]1=[O:33]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[C:28]([CH3:32])([CH3:31])[C:29](=[O:30])[N:25]([CH3:24])[C:26]4=[O:33])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CN1C(=O)NC(C)(C)C1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)nc3)CC2)c(C)c1
Yield: 64.2 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (112 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6].[Cl:10][C:11]1[N:16]=[C:15]([C:17]([NH2:19])=[O:18])[CH:14]=[C:13](Cl)[N:12]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:17]([C:15]1[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([NH:2][CH2:3][C@H:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6])[CH:14]=1)(=[O:18])[NH2:19]
Reactant: COC(=O)[C@@H](O)CN
Reactant: NC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@@H](O)CNc1cc(C(N)=O)nc(Cl)n1
Temperature: 50 °C
Yield: 76.1 %

Procedure:
To a mixture of the (S)-methyl 3-amino-2-hydroxypropanoate hydrochloride (0.333 g, 2.14 mmol) in acetonitrile (10 mL) was added 2,6-dichloropyrimidine-4-carboxamide (0.385 g, 2.01 mmol) and iPr2NEt (0.77 mL, 4.4 mmol). The mixture was heated at 50° C. overnight then cooled. The precipitated solid was filtered off, rinsed once with 2 mL acetonitrile, and air-dried to give (S)-methyl 3-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)-2-hydroxypropanoate as a pale peach-colored powder (0.421 g, 1.53 mmol, 76% yield). LC/MS: m/z=275.1 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([CH3:18])([O:12][CH2:13][C:14](OC)=[O:15])[C:9](=[O:11])[CH3:10]>C(OCC)C>[CH3:7][C:8]1([CH3:18])[C:9](=[O:11])[CH2:10][C:14](=[O:15])[CH2:13][O:12]1
Reactant: COC(=O)COC(C)(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC1(C)OCC(=O)CC1=O
Reaction time: 0.17 h

Procedure:
A solution of potassium tert-butoxide (1M in tert-butanol, 12.1 mL, 12.1 mmol) in diethyl ether (7.5 mL) at 0° C. under N2 gas was treated with a solution of the product from Example 66B in diethyl ether (3 mL). After 10 minutes, the reaction mixture was quenched into 2N HCl (25 mL) and extracted with diethyl ether (3×25 mL). The organic layers were combined, washed with brine, dried over Na2SO4, concentrated to an oil, treated with 10% dichloromethane in hexane (5 mL), and placed in the freezer for 1 hour. The resulting crystals were collected by filtration, washed with a cold solution of 10% dichloromethane in hexane, and dried to provide the title compound (431 mg).
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[C:4]2[CH:25]=[CH:26][S:27][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1.C1(C)C=CC=CC=1>[S:37]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[C:4]2[CH:25]=[CH:26][S:27][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccsc2c1=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccsc2c1=S
Temperature: 25 °C

Procedure:
Ethyl 4-oxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4-dihydrothieno[3,2-c]pyridazine-3-carboxylate (37 mg, 0.097 mmol) suspended in dioxane (5 mL) and toluene (5 mL), placed into an oil bath preheated at 110° C. and treated with Lawesson's Reagent (39 mg, 0.097 mmol, 1 equiv) portionwise over 10 minutes. The mixture was heated for an additional 30 minutes, cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 25:75; hexanes:ethyl acetate), providing the titled compound as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:29]=[CH:30][N:31]=2)[C:15]([NH:17][NH:18]C(OCC2C=CC=CC=2)=O)=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>[Pd].O1CCCC1>[NH:17]([C:15]([C:14]1[CH:29]=[CH:30][N:31]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=1)=[O:16])[NH2:18]
Reactant: O=C(CCc1ccccc1)Nc1cc(C(=O)NNC(=O)OCc2ccccc2)ccn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NNC(=O)c1ccnc(NC(=O)CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of benzyl 2-[2-[(3-phenylpropanoyl)amino]isonicotinoyl]hydrazinecarboxylate (1.10 g, 2.63 mmol), 10% palladium on carbon (50 mg), methanol (20 mL) and tetrahydrofuran (20 mL) was stirred under a hydrogen atmosphere at room temperature 18 hr. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (748 mg, yield 100%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH:18]S(O)(=O)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:8]([NH2:9])=[O:18])=[N:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ncccc1Oc1cc(Br)cnc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ncccc1Oc1cc(Br)cnc1C(N)=O
Reaction time: 8 h
Yield: 69 %

Procedure:
To 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 52 mmol) was added concentrated H2SO4 (30 mL) and the slurry was stirred overnight, at which point the material was fully dissolved. The reaction was poured into 0° C. water in small portions. While maintaining the temp below 20° C., the aqueous layer was basified by the addition of NaOH pellets, to a pH of about 5, at which point a solid formed. The solid was filtered, and the remaining aqueous layer was extracted with EtOAc. The organic layers, combined with the solid, were washed with brine, dried over MgSO4 and concentrated in vacuo to yield 5-bromo-3-(2-methylpyridin-3-yloxy)picolinamide (11 g, 69%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]3)[O:3]1.[CH:21](I)([CH3:23])[CH3:22]>>[CH:21]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([B:4]3[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)[C:15]1=[O:19])([CH3:23])[CH3:22]
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Reactant: CC(C)I
Product: CC(C)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 9, Step 1 starting from 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one and isopropyl iodide. LCMS (M+H)+=316.1.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C1COCC1>[C:1]1([O:7][C:8]2[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[C:10]([C:17]([F:18])([F:19])[F:20])[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(Oc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 4-(phenyloxy)-2-(trifluoromethyl)benzoic acid (for a preparation see Intermediate 35)(0.507 g, 1.80 mmol), in THF (40 ml), under nitrogen, was added borane-tetrahydrofuran complex (0.463 g, 5.39 mmol, Aldrich) carefully over about 2 min. The solution was stirred for 40 min at ambient temperature and then heated at gentle reflux for 20 h. To the mixture at ambient temperature was added methanol (10 ml) dropwise and then the solution was heated to reflux for 30 min. The solvent was evaporated in vacuo and the residue acidified with dilute aqueous HCl. The mixture was extracted with chloroform and the phases separated using a hydrophobic frit. The solvent was evaporated in vacuo to leave [4-(phenyloxy)-2-(trifluoromethyl)phenyl]methanol as a colourless oil (0.491 g). [4-(phenyloxy)-2-(trifluoromethyl)phenyl]methanol (0.491 g, 1.83 mmol) in dichloromethane (10 ml) under nitrogen was stirred and cooled to −5° C. A solution of phosphorus tribromide (0.173 ml, 1.831 mmol) in DCM (3.5 ml) was then added dropwise over about 10 min. The solution was then allowed to warm to room temperature and stirred for 4 h. A saturated solution of aqueous sodium bicarbonate (10 ml) was then added and the mixture stirred vigorously. The emulsion was further diluted with water and chloroform. The phases were separated using a hydrophobic frit. The aqueous phase was further extracted with chloroform. The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was re-dried with (MgSO4), filtered and the solvent removed in vacuo to give 4-(bromomethyl)-3-(trifluoromethyl)phenyl ether as a colourless oil (0.518 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Sc3ccc(Cl)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 305 was used, starting from 4-chloro-benzenethiol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenylsulfanyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 367 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:18])[CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:17][CH2:16][CH2:15][CH:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1)[CH3:18])(=[O:29])=[O:28]
Reactant: CC(CCO)N1CCN(c2ccc(F)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CCOS(C)(=O)=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(4-(4-fluorophenyl) piperazin-1-yl) butan-1-ol (prepared according to procedure reported in U.S. Pat. No. 5,021,420, 3.5 g, 13.87 mmol) in dichloromethane (30 ml) was added triethylamine (4.2 g, 41.61 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0-5° C. Methane sulfonyl chloride (1.58 g, 13.87 mmol) was added at 0-5° C. dropwise in 20 mins. The reaction mixture was stirred at same temp for 1 h. Progress of reaction was monitored by TLC. The reaction mixture was diluted with dichloromethane (20 ml) and washed with water (3×20 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain title compound (4.2 g) which was used for the next reaction without further purification.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][S:13](O)(=[O:15])=[O:14]>O>[O:11]=[C:3]1[NH:4][C:5]2[CH:10]=[C:9]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:8]=[CH:7][C:6]=2[S:1][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1CSc2ccccc2N1
Solvent: O
Product: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
4H-Benzo[1,4]thiazin-3-one (7.0 g) was added cautiously portionwise to chlorosulfonic acid (15 ml) at 0° C. over 20 minutes and the solution was stirred cold for 1 hour and then heated at 45° C. for 2 hours. It was cooled and poured slowly into iced-water. The product was collected, washed well with water and dried in vacuo to give a white solid (7.0 g).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#CCN(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.6 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-propionic acid methyl ester (563 mg, 1.80 mmol) in methanol (10 mL) and water (10 mL) was treated with lithium hydroxide (862 mg, 20.5 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (40 mL). This solution was acidified to pH=5 with concentrated hydrochloric acid and then extracted with ethyl acetate (1×40 mL) and chloroform/methanol (3:2, 1×50 mL). The combined organic extracts were then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-propionic acid (456 mg, 84%) as a brown foam: EI-HRMS m/e calcd for C19H25NO2 (M+) 299.1885, found 299.1885.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:26](=[O:28])(=[O:27])[N:25]([CH3:30])[CH3:24])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Yield: 61.1 %

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (100 mg, 0.336 mmol) and dimethylsulfamoyl chloride (144 mg, 1.01 mmol) affords 83 mg (61%) of the title compound as a white solid. MS (ES) 427 (M+Na), 403 (M−H); HPLC shows 87% purity.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH:19][CH2:20][CH2:21][S:22][CH3:23])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:23][S:22]([CH2:21][CH2:20][NH:19][C:15]1[C:16]2[CH:17]=[CH:18][C:9]([NH:8][CH2:7][C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCNc1cccc2nc(NCc3ccc(C)o3)ccc12
Solvent: ClCCl
Product: Cc1ccc(CNc2ccc3c(NCCS(C)=O)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(5-Methyl-furan-2-ylmethyl)-N5-(2-methylsulfanyl-ethyl)-quinoline-2,5-diamine (200 mg, 0.61 mmol) were dissolved in 6.5 mL dichloromethane and meta-chloro-perbenzoic acid was added (220 mg, 1.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of 10 mL water and 10 mL 2N sodium carbonate solution. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The reaction mixture was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient). The title compound was obtained as a white solid (60 mg, 29%), MS: m/e=344.3 (M+H+) together with N5-(2-methanesulfonyl-ethyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,5-diamine.