Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[C:16](O)(=[O:26])[C:17]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][O:20][C:19]=2[CH:18]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCCl>[CH2:21]1[O:22][C:23]2[CH:24]=[CH:25][C:17]([C:16]([C:6]3[CH:7]=[C:8]4[O:9][CH2:1][O:2][C:3]4=[CH:4][C:5]=3[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[O:26])=[CH:18][C:19]=2[O:20]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: COC(=O)C(C)c1ccc2c(c1)OCO2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Product: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccc3c(c1)OCO3)OCO2
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a mixture of methyl 2-(3,4-methylenedioxyphenyl)propionate (1 g, 4.8 mmol) in 1,2-dichloroethane (50 mL) was added piperonylic acid (1.6 g, 9.6 mmol) and P2O5 (4 g). The reaction mixture was stirred for 15 h and then poured to ice water (200 mL) and the product was extracted with EtOAc (2×100 mL). The pure product was obtained by flash chromatography (453 mg, 27%). 1H NMR (CDCl3) 7.37 (s, 1H), 7.33 (d, J=8.0, 1H), 6.95 (s, 1H), 6.83 (d, J=8.0, 1H), 6.76 (s, 1H), 6.07 (s, 2H), 6.02 (s, 2H), 3.95 (q, J=7.1, 1H), 3.58 (s, 3H), 1.45 (d, J=7.1, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][OH:6])#[CH:2].[CH3:11][Si:12](Cl)([CH3:14])[CH3:13]>C(N(CC)CC)C>[CH3:11][Si:12]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:1]#[CH:2])([CH3:14])[CH3:13]
Reactant: C#Cc1ccccc1CO
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: C#Cc1ccccc1CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
970 mg of 2-ethynyl-benzyl alcohol were dissolved in 50 ml of diethyl ester. 1.9 ml of triethylamine was added, followed by dropwise addition of 0.9 ml of trimethylsilyl chloride. The reaction mixture was stirred at room temperature for 4 hours, poured onto ice/5% aqueous sodium bicarbonate and extracted with ether. The oily residue obtained after drying and evaporation of the solvent was distilled to give 1.3 g of 2-ethynylbenzyl trimethylsilyl ether as a colourless oil, b.p. 85-89° C./0.8 mm.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH:8]1([N:13]2[C:18]3=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH:34]=[CH:33][CH:32]=[N:31]5)=[CH:26][CH:25]=4)=[N:21][CH:22]=[C:17]3[CH2:16][NH:15][C:14]2=[O:35])[CH2:12][CH2:11][CH2:10][CH2:9]1.CC(C)([O-])C.[K+]>C1COCC1>[CH:8]1([N:13]2[C:18]3=[N:19][C:20]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH:34]=[CH:33][CH:32]=[N:31]5)=[CH:28][CH:29]=4)=[N:21][CH:22]=[C:17]3[CH:16]=[N:15][C:14]2=[O:35])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C1NCc2cnc(Nc3ccc(-n4cccn4)cc3)nc2N1C1CCCC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1ncc2cnc(Nc3ccc(-n4cccn4)cc3)nc2n1C1CCCC1
Yield: 40 %

Procedure:
Prepared from 100 mg (0.20 mmol) of the trifluoroacetate salt of 1-cyclopentyl-7-[4-(pyrazol-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 115 mg (1.02 mmol) of potassium tert-butoxide in 5.0 mL of THF. The semi-solid residue is triturated in diethyl ether, and the orange amorphous solid is collected and dried to give 31 mg (40%) of the title compound: mp>135° C. (dec).
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[CH:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16]>>[CH3:16][C:10]1[CH:9]=[C:14]([CH:13]=[CH:12][CH:11]=1)[O:15][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)N1CC(O)C1
Reactant: Cc1cccc(O)c1
Product: Cc1cccc(OCC(O)CNC(C)C)c1
Yield: 81 %

Procedure:
1-(iso-propyl)-3-azetidinol and m-cresol were reacted in the same manner as in Example 7 to yield 1-(3'-methyl-phenoxy)-3-(iso-propylamino)-2-propanol melting at 80°-82° C. The yield was 81%.
Reaction SMILES: C1C2C(OC(=O)[N:16](C)[CH2:17][C:18](=[O:45])[NH:19][C:20]3[C:29]([NH2:30])=[C:28]4[C:23]([C@@H:24]([C:34]5[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([Br:44])[CH:35]=5)[C:25]([C:32]#[N:33])=[C:26]([NH2:31])[O:27]4)=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(Cl)Cl.[OH-].[Na+]>CO>[NH2:16][CH2:17][C:18]([NH:19][C:20]1[C:29]([NH2:30])=[C:28]2[C:23]([C@@H:24]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([Br:44])[CH:35]=3)[C:25]([C:32]#[N:33])=[C:26]([NH2:31])[O:27]2)=[CH:22][CH:21]=1)=[O:45]
Reactant: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(NC(=O)CN(C)C(=O)OC2c4ccccc4-c4ccccc42)c3N)cc(Br)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(NC(=O)CN)c3N)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To an oven-dried one-neck round bottom reaction flask charged with a magnetic stir bar at rt under argon was added (9H-fluoren-9-yl)methyl((R)-2,8-diamino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-4H-chromen-7-ylcarbamoyl)methylcarbamate (0.050 g, 0.072 mmol), CH2Cl2:MeOH, 1:1 (2.40 mL) and 2N NaOH (0.072 mL, 0.14 mmol). The orange suspension was stirred at rt overnight. The suspension was concentrated leaving a brown residue. The residue was extracted with CHCl3 (3×40 mL), dried over MgSO4, filtered and concentrated to give the crude product. Purification by flash column chromatography (silica gel 4 g pre-packed column, gradient elution with CH2Cl2:MeOH, 96:4 to 90:10 with trace Et3N) gave 0.012 g (35%) of the title compound as a yellow solid: 1H-NMR (CDCl3): 9.34 (br s, 1H), 6.90 (d, J=1.9 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 6.37 (d, J=8.2 Hz, 1H), 4.72 (br s, 2H), 4.64 (s, 1H), 4.29 (br s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.54 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][C@H:15]([CH3:17])[NH:14][C:13]2=[O:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CC(=O)CC>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:14]2[C@@H:15]([CH3:17])[CH2:16][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[C:13]2=[O:18])=[CH:28][CH:27]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2C[C@H](C)NC2=O)nc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1sc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 87.3 %

Procedure:
To a solution of (S)-ethyl 4-methyl-2-(4-methyl-2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (0.45 g, 1.67 mmol) in 2-butanone (20.0 mL) was added cesium carbonate (1.09 g, 3.34 mmol) and 4-fluorobenzyl bromide (0.40 g, 2.09 mmol). The reaction mixture was refluxed for 16 h, filtered and washed with acetone (150 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluted with 2-5% methanol in dichloromethane to afford the title compound as a colorless solid (0.55 g, 87%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.35 (m, 2H), 7.21-7.15 (m, 2H), 4.60 (d, J=15.6 Hz, 1H), 4.31 (d, J=15.6 Hz, 1H), 4.26-4.17 (m, 3H), 3.79-3.72 (m, 1H), 3.57 (dd, J=10.3, 6.7 Hz, 1H), 2.52 (s, 3H), 1.27 (t, J=7.1 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 377.9 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[NH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:19]([O:18][C:16](=[O:17])[CH2:15][NH:14][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1ccnc(C=O)c1
Reactant: CC(C)(C)OC(=O)CN
Product: CCOC(=O)c1ccnc(CNCC(=O)OC(C)(C)C)c1

Procedure:
Prepared by General Procedure A from ethyl 2-formylpyridine-4-carboxylate and tert-butyl 2-aminoacetate. Title compound isolated as yellow oil by column chromatography (EtOAc/hexanes). 1H-NMR (300 MHz, MeOH-d4): δ 8.7 (d, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 4.4 (s, 2H), 4.3 (q, 2), 3.8 (s, 2H), 3.3 (s, 2H), 1.4 (s, (H), 1.3 (t, 3H). ES-MS: 295 [M+1].
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li+].[OH-]>C1COCC1.O>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C(C)c1ccc2c(c1)CCN2S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)CCN2S(C)(=O)=O
Reaction time: 12 h
Yield: 80 %

Procedure:
the propanoate (1.78 mmol, 0.53 g) obtained in step b was dissolved in a THF-water mixture (5 ml, 2:1), LiOH (5.34 mmol, 0.128 g) was added and refluxing was carried out for 12 h. The reaction mixture was extracted with diethyl ether (25 ml), the aqueous phase was acidified to pH 2 with 1 N HCl and extraction was carried out with EE (3×25 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed in a vacuum. It was possible to obtain 2-(1-(methylsulphonyl)indolin-5-yl)propanoic acid in an 80% yield (0.382 g).
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)=[O:6])[CH3:3].[CH:14]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:18]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][CH:9]=2)=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Reactant: O=C(Cl)C1CCC1
Agent: [I-]
Product: CCOC(=O)c1ccc(C(=O)C2CCC2)cc1

Procedure:
Intermediate i-4a was prepared from 4-ethoxycarbonylphenyl zinc iodide and cyclobutanecarbonyl chloride following the above procedure as described for intermediate i-1a. 1HNMR (500 MHz, CDCl3): δ 8.13 (d, 2H, J=8.2 Hz), 7.96 (d, 2H, J=8.3 Hz), 4.43 (q, 2H, J=7.1 Hz), 4.04 (dt, 1H, J=6.9, 7.4 Hz), 2.44 (m, 2H), 2.34 (m, 2H), 2.14 (m, 1H), 1.96 (m, 1H), 1.43 (t, 3H, J=7.0 Hz).
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].Cl.[CH2:37]([OH:41])[CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][CH2:37][O:41][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Reactant: OCCCO
Agent: Cl
Agent: [Na]
Product: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2ccccc2)nc(-c2ncccn2)nc1OCCCO
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 80.5 %

Procedure:
Sodium (1.031 g) was dissolved in 20.130 g of 1,3-propanediol and 2.091 g of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide was added thereto with stirring at room temperature. The reaction mixture was stirred at room temperature for 50 minutes and then at 60° C. for 50 minutes and poured into a mixture of 1N hydrochloric acid and ice. This was extracted with ethyl acetate and the ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by a silica gel column chromatography (chloroform-methanol=100:1 to 20:1). The resulting syrup was crystallized in ether and collected by filtration to give 1.817 g of N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[Na+].[C:12]1([S:18]([O-:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=2[CH:6]=[O:7])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1F
Agent: [Na+]
Product: O=Cc1ccc(Cl)cc1S(=O)(=O)c1ccccc1

Procedure:
The title compound was prepared by the method of Preparation 5a using 4-chloro-2-fluorobenzaldehyde and benzene sulfinic acid sodium salt.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[Cl:39][C:40]1[CH:41]=[C:42]([C:48]2([C:64]([F:67])([F:66])[F:65])[O:52][N:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:59]4([F:63])[CH2:62][NH:61][CH2:60]4)=[CH:55][CH:54]=3)[CH2:49]2)[CH:43]=[C:44]([Cl:47])[C:45]=1[F:46]>CN(C=O)C>[Cl:39][C:40]1[CH:41]=[C:42]([C:48]2([C:64]([F:65])([F:66])[F:67])[O:52][N:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:59]4([F:63])[CH2:62][N:61]([C:1](=[O:6])[CH2:2][CH2:3][CH3:4])[CH2:60]4)=[CH:55][CH:54]=3)[CH2:49]2)[CH:43]=[C:44]([Cl:47])[C:45]=1[F:46]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc(C4(F)CNC4)cc3)=NO2)cc1Cl
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of butyric acid (50 mg) in DMF (5 mL) was added HATU (200 mg) then triethyl amine (150 μL). The resulting solution was stirred at ambient temperature for 15 minutes then 5-(3,5-dichloro-4-fluorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole hydrochloride (Preparation 16 100 mg) was added in one portion. Reaction stirred at ambient temperature for 16 hours. Solvent was removed in vacuo and the residue partitioned between water (10 mL) and CH2Cl2 (10 mL). Organic phase collected and condensed. The crude material was adsorbed on silica and chromatographed on a 12 g silica column, eluting with a gradient of 0% to 100% ethyl acetate in heptane. Fractions containing the desired material were combined and concentrated. Et2O (˜½ mL) was added to the resulting film. Placing the flask on high vacuum overnight resulted in formation of a white foam. Yield 86 mg (80%). 1H NMR (CDCl3) δ 7.75 (d, 2H), 7.61 (d, 2H), 7.55 (d, 2H), 4.68-4.33 (m, 4H), 4.12 (d, 1H), 3.72 (d, 1H), 2.19 (m, 2H), 1.73 (m, 2H), 1.01 (m, 3H). LC/MS retention time=3.688 minutes, MS calculated for (C23H19Cl2F5N2O2), 520.07; found 521.0 M+H.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:18]=[C:19]=[S:20])[C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:24])[CH2:22][NH2:23]>C(Cl)Cl>[NH2:23][CH2:22][CH2:21][NH:24][C:19](=[S:20])[NH:18][C:14]1[C:15]([CH3:17])=[C:16]2[C:11]([CH2:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:12][CH:13]=1
Reactant: Cc1c(N=C=S)ccc2c1N(C(=O)OC(C)(C)C)CC2
Reactant: NCCN
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
A solution of the above crude 1-t-butoxycarbonyl-2,3-dihydro-6-isothiocyanato-7-methylindole (0.59 g) in methylene chloride (10 mL) is slowly added to a solution of ethylenediamine (0.60 g, 10 mmol) in methylene chloride (10 mL). After 30 minutes, the solution is washed with four 50-mL portions of aqueous potassium carbonate, dried over anhydrous potassium carbonate, filtered and rotary evaporated to yield 6-[N'-(2-aminoethyl)thioureido]-1-t-butoxycarbonyl-2,3-dihydro-7-methylindole as an amber glassy solid (0.72 g). This material is taken on into the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=3)(=[O:32])=[O:31])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 100 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.0 g, 3.0 mmol) and 3-fluorobenzenesulfonyl chloride (0.60 mL, 4.5 mmol) the title compound of Step A was obtained (1.46 g, 2.99 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 7.48-7.65 (m, 4H), 7.37 (t, J=7.7 Hz, 1H), 7.20-7.28 (m, 3H), 6.97 (d, J=5.1 Hz, 1H), 3.30-3.37 (m, 1H), 1.38 (d, J=7.0 Hz, 6H). MS (ESI): 489.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.[H-].[Na+].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27](=O)[CH3:28]>CN(C=O)C.O>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]=[C:27]([C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])[CH3:28]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: CCOP(=O)(Cc1ccccc1Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cc1ccccc1Cl)c1ccc(F)cc1F
Temperature: 3 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
At 3° C., a solution of diethyl 2-chlorobenzylphosphonate (2.00 g, 7.61 mmol) in dry DMF (30 ml) was added to a stirred suspension of sodium hydride (60% by weight suspension in mineral oil, 365 mg, 9.13 mmol; freshly washed with dry heptane) in dry DMF (20 ml). After 1 h of stirring at 3° C., a solution of 2′,4′-difluoroacetophenone (1.31 g, 8.37 mmol) in dry DMF (20 ml) was added dropwise. The resulting mixture was stirred at RT for 68 h and then diluted with water and extracted with diethyl ether. The organic phase was dried and concentrated to dryness under reduced pressure, and the residue was purified by chromatography on silica gel, which gave 1-[1-(2-chlorophenyl)prop-1-en-2-yl]-2,4-difluorobenzene as a 93/7 mixture of diastereoisomers [colourless solid, 560 mg, yield 26%; GC/MS: m/z=264 (M+); HPLC/MS: log P(HCOOH)=5.05 (major diastereoisomer), 5.34 (minor diastereoisomer)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2[O:33][C:32]([C:34](O)=[O:35])=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:34]([C:32]4[O:33][C:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=5)=[CH:30][CH:31]=4)=[O:35])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 95.9 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (24 mg, 0.085 mmol), 5-(3-chlorophenyl)-2-furoic acid (9.5 mg, 0.043 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.085 mmol), HOBT (12 mg, 0.085 mmol) and DIPEA (15 μl, 0.085 mmol) in DMF (4 ml) were stirred at room temperature for 4 h. The DMF was evaporated under vacuum and the residue partitioned between ethyl acetate and water. The organic fraction was concentrated under vacuum and the residue purfied by preparative HPLC to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-5-(3-chlorophenyl)-2-furamide (20 mg, 95%). NMR; δH [2H6]—DMSO 10.25,(1H, s), 8.64,(1H, t), 8.11,(1H, t), 7.96-7.94,(3H, m), 7.75,(1H, dd), 7.66,(1H, d), 7.52,(1H, t), 7.49-7.44,(3H, m), 7.39,(1H, d), 7.34-7.31,(2H, m), 3.18,(2H, t), 2.23,(3H, s), 1.06,(1H, m), 0.45,(2H, m), 0.26,(2H, m). LCMS: retention time 3.88 min, MH+485.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:10]2[CH3:19])=[C:4]([N+:20]([O-])=O)[CH:3]=1.O1CCCC1.[H][H]>[Ni].CO>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:10]1[CH3:19]
Reactant: COC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])C(C)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N1CCC(Nc2ccc(Cl)cc2N)C(C)C1

Procedure:
A mixture of 51 parts of methyl 4-(4-chloro-2nitrophenylamino)-3-methyl-1-piperidinecarboxylate, 270 parts of tetrahydrofuran and 96 parts of methanol is hydrogenated at normal pressure and at normal temperature with 15 parts of raney-nickel catalyst. After the calculated amount of hydrogen is taken up (6 hours), the catalyst is filtered off and the filtrate is evaporated. The oily residue is triturated in warm 2,2'-oxybispropane. After cooling, the product is filtered off, pulverized in a mortar and triturated again in 2,2'-oxybispropane. The product is filtered off and dried, yielding methyl 4-(2-amino-4-chlorophenylamino)-3-methyl-1-piperidinecarboxylate.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a stirred solution of 2-cyclopropylethanol (5.00 g, 58.05 mmol) in dichloromethane (20 mL) was added pyridine (7.03 mL, 86.92 mmol), followed by p-toluenesulfonyl chloride (10.50 g, 55.07 mmol). The reaction mixture was stirred for 16 h, and then partitioned between dichloromethane (100 mL) and water (50 mL). The organic layer was washed with 10% aqueous hydrochloric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford 2-cyclopropylethyl 4-methylbenzenesulfonate as a colorless oil (11.90 g, 96%): 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 4.09 (t, J=6.6 Hz, 2H), 2.45 (s, 3H), 1.57-1.48 (m, 2H), 0.74-0.59 (m, 1H), 0.45-0.36 (m, 2H), 0.08-0.06 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[CH:20]=3)[C:15]2=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1.[NH:32]1[CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH:10]2[CH2:11][CH2:12][N:8]([C:7]3[CH:6]=[CH:5][C:4]([N:14]4[CH:23]=[CH:22][C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@H:26]6[CH2:30][CH2:29][CH2:28][O:27]6)[CH:20]=5)[C:15]4=[O:31])=[CH:3][C:2]=3[F:1])[CH2:9]2)[CH2:35][CH2:34][CH2:33]1
Reactant: O=C1CCN(c2ccc(-n3ccc4cc(OC[C@H]5CCCO5)ccc4c3=O)cc2F)C1
Reactant: C1CNC1
Product: O=c1c2ccc(OC[C@H]3CCCO3)cc2ccn1-c1ccc(N2CCC(N3CCC3)C2)c(F)c1

Procedure:
2-[3-Fluoro-4-(3-oxo-pyrrolidin-1-yl)-phenyl]-6-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-2H-isoquinolin-1-one was reacted with azetidine according to Method J1. In this way the product was obtained with molecular weight 463.23 (C27H30FN3O3); MS (ESI): 464 (M+H+).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][O:14][C:15]([C:17]([CH3:34])([CH3:33])[CH2:18][CH2:19][C:20]([O:22]CC2C=CC([N+]([O-])=O)=CC=2)=[O:21])=[O:16])=[CH:11][CH:10]=1>O.O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]([C:17]([CH3:33])([CH3:34])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[CH:35][CH:36]=1
Reactant: COc1ccc(COC(=O)C(C)(C)CCC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)C(C)(C)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
To a solution of sodium sulfite hydrade (12.35 g) in water (70 ml) was added a solution of p-nitrobenzyl 4-p-methoxybenzyloxycarbonyl-4-methylvalerate (25.4 g) in tetrahydrofuran (140 ml). The reaction mixture was stirred at room temperature for 7.5 hours, diluted with water and washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give 4-p-methoxybenzyloxycarbonyl-4-methylvaleric acid.