Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH2:41][CH3:42])([C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([CH3:40])[CH:34]=3)[CH2:31][CH3:32])=[CH:26][C:25]=2[CH3:43])=[C:21]([CH3:23])[CH:22]=1)=[O:17].C(OCC)C>CN(C)C=O>[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:35]([CH3:40])[CH:34]=3)([CH2:31][CH3:32])[CH2:41][CH3:42])=[CH:26][C:25]=2[CH3:43])=[C:21]([CH3:23])[CH:22]=1)=[O:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(-c2sc(C(=O)OC)cc2C)c(C)c1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1ccc(-c2sc(C(=O)OC)cc2C)c(C)c1
Reaction time: 0.2 h
Yield: 88285 %

Procedure:
t-Butyldimethylsilyl chloride (36 mg, 0.238 mmol) and imidazole (40.5 mg, 0.595 mmol) were added to a solution of 5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-4-methyl-thiophene-2-carboxylic acid methyl ester (Example 20-(1); 50.3 mg, 0.119 mmol) in N,N-dimethylformamide (0.2 mL) at room temperature, and the mixture was stirred at the same temperature for 0.2 hour. Diethyl ether was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=95/5 to ethyl acetate only) to give the title compound (56.4 g, 88.3%).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:13]([CH3:12])[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: CNCCN(C)C
Agent: N
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCN(C)c1nnc2ccc(F)cn12
Temperature: 170 °C
Yield: 46 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and N,N′,N′-trimethylethane-1,2-diamine (900 mg, 8.77 mmol) in NMP (2 mL) was heated in the microwave at 170° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as a brown oil (190 mg, 46%). LCMS (Method 4): Rt 0.38 min, m/z 238 [MH+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10]N)[CH:6]=[CH:7][C:8]=1[Cl:9].C[CH:13](C)[CH2:14][CH2:15][C:16]([OH:18])=[O:17].[CH2:20]([OH:24])[CH2:21][CH2:22][CH3:23].[OH-].[Na+]>O>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]2[C:4]=1[C:14]([CH2:15][C:16]([O:18][CH3:20])=[O:17])=[CH:13][NH:10]2.[Cl:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[Cl:2])[NH:10][CH:23]=[C:22]2[CH2:21][C:20]([O:17][CH2:16][CH2:15][CH2:14][CH3:13])=[O:24]
Reactant: CC(C)CCC(=O)O
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: CCCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCOC(=O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Product: COC(=O)Cc1c[nH]c2ccc(Cl)c(Cl)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With 5.81 g of 3,4-dichlorophenylhydrazine hydrochloride was mixed 11.57 g of 4,4-dimethylbutyric acid, and the resulting mixture was sufficiently stirred to obtain a transparent solution, after which 7.64 g of n-butanol was added. The mixed solution was stirred with treating at 110 C. for 1 hour. The reaction solution was cooled to room temperature, diluted with water, and neutralized with a 1N aqueous sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the ethyl acetate phase was washed with distilled water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the oily substance thus obtained was purified by a silica gel column chromatography and a silica gel thin-layer chromatography to obtain 0.28 g of methyl 4,5-dichloroindole-3-acetate and 0.395 g of n-butyl 5,6-dichloroindole-3-acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]#[N:34])=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:22][CH:23]=1)#[N:34]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccccc4C#N)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-2-cyanobiphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided an off-white solid. 1H NMR: δ 7.93 (dd, J=7.0, 2.0 Hz, 2H), 7.75 (dd, J=7.7, 1.0 Hz, 1H), 7.64 (dt, J=1.3, 7.7 Hz, 1H), 7.42-7.50 (m, 4H), 7.31 (d, J=8.3 Hz, 2H), 7.07 (dd, J=7.1, 1.9 Hz, 2H), 4.00 (A of AB, J=13.7 Hz, 1H), 3.93 (s, 3H), 3.42 (B of AB, J=13.7 Hz, 1H) MS (m/e): 477.3 (M−H)+. Anal: Calc for C24H18N2O5S2.0.167 C3H9NO: 59.92% C, 4.00% H, 6.18% N; Found: 59.60% C, 4.04% H, 5.99% N.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)=[O:8].C1([CH:17]([N:19]2[CH2:22][CH:21]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:20]2)C)C=CC=CC=1.[CH2:30]([NH2:33])[CH:31]=[CH2:32]>C(Cl)Cl.C1C=CC=CC=1>[CH2:30]([NH:33][C:17]([N:19]1[CH2:20][CH:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:22]1)=[O:8])[CH:31]=[CH2:32]
Reactant: O=C(Cl)Cl
Reactant: C=CCN
Reactant: CC(c1ccccc1)N1CC(Oc2ccccn2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: C=CCNC(=O)N1CC(Oc2ccccn2)C1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 10 g (0.072 mole) of finely ground potassium carbonate in 90 ml of methylene chloride was added 32 ml (0.062 mole) of 2M phosgene in benzene. The mixture was stirred for 15 min and 8 g (0.031 mole) of 1-(1-phenylethyl)-3-(2-pyridyloxy)azetidine in 50 ml of methylene chloride was added. The mixture was stirred at 25° C. for 2 hr and concentrated on a rotary evaporator at 25° C./30 mm and the residue was treated with 100 ml of tetrahydrofuran. The stirred mixture was cooled with an ice bath and treated dropwise with 4 g (0.07 mole) of allyl amine. After stirring 30 min at 25° C., the material was partitioned between water and methylene chloride. The methylene chloride was dried and concentrated. The residue was chromatographed on a Waters® PREP-500 HPLC using a silica column and eluting with 50% ethylacetate-hexane. The product was crystallized twice from isopropyl ether. Yield of title compound was 1.5 g (21%), m.p. 72°-76° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:8][CH:9]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(OC(F)(F)F)cc1

Procedure:
4-(trifluoromethoxy)phenol (1.36 ml, 10.6 mmol), 2-fluoro-1-nitrobenzene (0.74 ml, 7 mmol), potassium carbonate (1.46 g, 10.5 mmol) were mixed together in DMF (4 ml) and heated at reflux for 5 h. Allowed to cool, and evaporated in-vacuo. Residue partitioned between diethyl ether and sodium hydroxide (1 M). Organic layers combined and dried over anhydrous magnesium sulphate and evaporated in-vacuo, to afford a yellow oil, 2.34 g, >100%. Rf: 0.72 (DCM), 1HNMR (CDCl3, 270 MHz) δ 7.03 (3H, m, Ar HD, Ar HF), 7.20 (2H, dd, J=0.9, 10.1 Hz, Ar HE), 7.23 (1H, m, Ar HB), 7.53 (1H, m, Ar HC), 7.97 (1H, dd, J=1.5, 8.2 Hz, Ar HA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[O:5][C:6]1[CH:13]=[C:12]([C:14]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)([OH:39])[C:15]2[N:16]=[CH:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[O:5][C:6]1[CH:13]=[C:12]([C:14]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)([OH:39])[C:15]2[NH:16][CH:17]=[N:18][CH:19]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(C(O)(c2ccc(Cl)cc2)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1Oc1cccc(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(O)(c2ccc(Cl)cc2)c2cnc[nH]2)cc1Oc1cccc(Cl)c1

Procedure:
2-(3-Chloro-phenoxy)-4-[(4-chloro-phenyl)-hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-benzonitrile (0.269 g, 0.396 mmol), trifluoroacetic acid (5 mL), triethylsilane (0.050 mL, 3.17 mmol) was stirred in CH2Cl2 (5 mL) under Ar for 2 hr. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with satd. NaHCO3 solution, water, brine, dried (MgSO4), concentrated and purified using SiO2 chromatography (1-1.5% MeOH/CH2Cl2 w NH4OH) to give the title compound. FAB MS (M+1)=436;
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[SH:39])[CH3:32]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:31][CH3:32])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:26][CH2:27]1)=[O:12])([CH3:7])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Reactant: CCc1ccccc1S
Agent: CS(=O)(=O)[O-]
Product: CCc1ccccc1S[C@@H]1C[C@@H](C(=O)NC2(C#N)CC2)N(C(=O)OC(C)(C)C)C1

Procedure:
The reaction of the mesylate from experiment A2 with 2-ethylbenzenethiol yielded (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2-ethyl-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless oil. MS: 414.4 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.C1(O)C2C=C[CH:17]=[C:16]([OH:21])[C:15]=2CC1.C(OC1C=CC=C2C=1CCC2O)(=O)C.C(C1OC1)Cl.[OH-].[Na+]>>[O:21]1[CH2:17][CH:16]1[CH2:15][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2
Reactant: O=C1CCc2c(O)cccc21
Reactant: Oc1cccc2c1CCC2O
Agent: CC(=O)Oc1cccc2c1CCC2O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCC1CO1
Product: C1=Cc2c(cccc2OCC2CO2)C1

Procedure:
4-Hydroxy-1-indene is prepared starting from 4-hydroxyindanone via 1,4-indanediol, 4-acetoxy-1-indanol and 4-acetoxy-1-indene in this order. The resulting 4-hydroxy-1-indene is allowed to react with epichlorohydrin in an aqueous solution of sodium hydroxide to give 4-(2,3-epoxypropoxy)indene. [cf. Yakugaku Zasshi 92, 1358 (1972)].
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[CH:36][C:28]=2[C:25]2[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=2)[NH:32][C:31]1=[O:37]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 72 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-pyridin-4-yl-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 3-methyl-5-(2-morpholin-4-yl-ethyl)-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (54 mg, 72.0%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:26](=[O:27])[C:25]1[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:23]([C:22]([F:21])([F:36])[F:37])[CH:24]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)CCNc1cnccc1-c1ccccc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow foam (36%). MS (ESI): m/z=551.06 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11].O1CCCC1.[F:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>C(N(CC)CC)C>[Cl:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)(=[O:26])=[O:25])[CH:3]=2)[NH:7][N:6]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc2[nH]nc(Cl)c2c1)c1cccc(F)c1
Yield: 37.2 %

Procedure:
N-(3-Chloro-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.18 g of 5-amino-3-chloro-1H-indazole, 20 ml of tetrahydrofuran, 0.25 ml of triethylamine and 0.23 g of 3-fluorobenzenesulfonyl chloride. 0.13 g of N-(3-chloro-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of a yellow foam which decomposes at approximately 80° C. (analysis C13H9ClFN3O2S % calculated: 47.93; H, 2.78; Cl, 10.88; F, 5.83; N, 12.90; O, 9.82; S, 9.84% found C, 48.11; H, 2.64; F, 5.14; N, 13.14; S, 8.22).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH2:15]([C:18]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1)([CH2:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH2:17]>>[CH2:15]([C:18]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]3)[CH:27]=1)([CH2:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH2:17]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: C=CCC(CC)(C(=O)OCC)c1cccc(O)c1
Product: C=CCC(CC)(C(=O)OCC)c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with ethyl 2-allyl-2-(3-hydroxyphenyl)butyrate to give ethyl 2-allyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyrate in 25% yield as a gum.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:38])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[N:33]4)[CH:27]=3)[CH2:24][C:23](=[O:38])[NH:22][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-c3cccc(F)c3F)cc2N1
Yield: 81 %

Procedure:
Prepared from {2′,3′-difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K95) (118 mg, 0.22 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (74 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].S(Cl)([Cl:24])(=O)=O>>[Cl:24][CH:14]([C:13](=[O:20])[CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Product: CCOC(=O)C(Cl)C(=O)CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared in a manner analogous to Intermediate 124 starting from ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate (Intermediate 25) and sulfuryl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[O:24])[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]1)=[N:9]2)=[O:4].Br[CH2:32][C:33]1[CH:37]=[C:36]([C:38]2[S:39][C:40]([Cl:43])=[CH:41][CH:42]=2)[O:35][N:34]=1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:25][CH2:26][C:27]([F:28])([F:29])[F:30])=[C:8]2[C:12]=1[N:11]([CH2:32][C:33]1[CH:37]=[C:36]([C:38]3[S:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[O:35][N:34]=1)[C:10]([C:13](=[O:24])[NH:14][CH:15]1[CH2:16][CH2:17][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:20]1)=[N:9]2)=[O:4]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1sc(OCC(F)(F)F)c2nc(C(=O)NC3CCN(C(C)C)CC3)[nH]c12
Product: COC(=O)c1sc(OCC(F)(F)F)c2nc(C(=O)NC3CCN(C(C)C)CC3)n(Cc3cc(-c4ccc(Cl)s4)on3)c12

Procedure:
3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-6-(2,2,2-trifluoro-ethoxy)-3H-thieno[3,4-d]imidazole-4-carboxylic acid methyl ester was prepared by a procedure according to example 81 starting from 68.0 mg (0.15 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-6-(2,2,2-trifluoro-ethoxy)-3H-thieno[3,4-d]imidazole-4-carboxylic acid methyl ester and 42.2 mg (0.15 mmol) 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole. Purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compound as its formiate in form of a white amorphous solid. Structural assignment was achieved by NOE-spectroscopy.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1.ClCCC1C=CC(S(C)=[O:23])=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH3:12])=[O:23])=[CH:9][CH:10]=1
Reactant: CSc1ccc(CCCCl)cc1
Reactant: CS(=O)c1ccc(CCCl)cc1
Product: CS(=O)c1ccc(CCCCl)cc1

Procedure:
12b was prepared from 11b (2.0 g; 10.0 mmol) using the method described in the synthesis of 12a. M.p.: 46° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[Cl:24][C:25]1[N:30]=[C:29]([C:31]([NH2:33])=O)[CH:28]=[C:27]([N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:41]([C:43]3[NH:44][C:45]([CH3:50])=[C:46]([Cl:49])[C:47]=3[Cl:48])=[O:42])[CH2:36][CH2:35]2)[N:26]=1.[CH3:51][Si:52]([O:55][P:56](=[O:58])=[O:57])([CH3:54])[CH3:53]>C1(C)C=CC=CC=1>[CH3:51][Si:52]([O:55][P:56](=[O:58])=[O:57])([CH3:54])[CH3:53].[Cl:48][C:47]1[C:46]([Cl:49])=[C:45]([CH3:50])[NH:44][C:43]=1[C:41]([NH:40][CH:37]1[CH2:38][CH2:39][N:34]([C:27]2[CH:28]=[C:29]([C:31]#[N:33])[N:30]=[C:25]([Cl:24])[N:26]=2)[CH2:35][CH2:36]1)=[O:42]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)nc(Cl)n3)CC2)c(Cl)c1Cl
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C#N)nc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 60 h

Procedure:
A stock solution of trimethylsilyl polyphosphate (prepared according to Yokoyama, Masataka; Yoshida, Sayaka; Imamoto, Tsuneo. Synthesis, 1982, 7, 591-592) was prepared by combining P2O5 (10 g) and hexamethyldisiloxane (25 ml) in anhydrous toluene (50 ml) and heating the mixture at 80° C. until it became a clear solution (about 45 minutes). 2-Chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxamide (Example 37, 2.1 g, 4.8 mmol) was treated with trimethylsilyl polyphosphate (80 ml), and the reaction was heated at 80° C. for 5 h, after which the reaction was about 50% complete. No further reaction was apparent after adding more trimethylsilyl polyphosphate and letting the reaction stir an additional 2.5 days. Upon cooling to room temperature, the reaction was concentrated under reduced pressure until most of the solvent was removed. The remaining liquid was triturated with EtOAc and water to form a brown precipitate, which was mostly the amide precursor. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid. About 20 mg was purified by preparatory HPLC, using a gradient of 35-75% acetonitrile/water (0.1% TFA), while the rest was carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([NH2:10])[CH2:8][O:7][CH2:6]1)=[O:4].Cl.[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]([CH:5]1[CH:9]([NH:10][S:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([CH3:12])[CH:22]=3)=[CH:26][CH:27]=2)(=[O:32])=[O:33])[CH2:8][O:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1COCC1N
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1COCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
To a slurry of 2.0 g (13.77 mmol) of 4-amino-tetrahydro-furan-3-carboxylic acid methyl ester [WO 01/70673, Examples 46, 58] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (5.13 g, 15.15 mmol) in CH2Cl2 (20 mL) was added saturated aqueous NaHCO3 (20 mL) at 0° C. The solution was allowed to warm to 25° C. over 19 h. The reaction was then diluted with CH2Cl2 (100 mL) and water (30 mL). The organic layer was washed with water (2×50 mL)and then dried over MgSO4, filtered and concentrated to obtain a crude oil (5.13 g ). The crude product was purified by Biotage Flash 40M chromatography, eluting with 1:1 ethyl acetate-hexanes, to afford 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid methyl ester as a white solid (2.3 g, 38%). MS: 457 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]1[CH2:33][OH:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH2:33][OH:34])[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: OC[C@H]1COCCN1
Product: CCOC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 60.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.6 g, 61%). The compound was characterized by the following spectroscopic data: