Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[CH:20]=1)=O.O=P(Cl)(Cl)[Cl:35].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:35][C:6]1[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]2[NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[C:24]([F:32])[CH:23]=4)[CH:20]=3)=[N:1][C:2]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(Cc3ccc(C(F)(F)F)c(F)c3)c2)c1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccc(C(F)(F)F)c(F)c4)c3)[nH]c2c1=O
Temperature: 127.5 °C
Yield: 50 %

Procedure:
A mixture of 1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.8 g, 1.76 mmol), POCl3 (25 ml) and PCl5 (0.2 g) were heated at 125-130° C. for 20 hours. Reaction mixture was cooled to 20-25° C. and it was concentrated under vacuum. To this reaction mixture brine (50 ml) was added and extracted with ethyl acetate (3×2 ml). The combined organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 2 to 4% methanol in DCM as an eluent to obtain 2-Chloro-8-[1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one (0.4 g, 50%) as a pale brown solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:34])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[N:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[N:31][CH:30]=[C:29]([CH3:33])[N:28]=4)[CH:22]=3)[CH2:18][C:17](=[O:34])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (4-chloro-5-methyl-2-{3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M116) (0.46 g, 0.93 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (270 mg, 77%).
Reaction SMILES: B.O1CCCC1.[C:7]([CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14])(O)=[O:8].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[OH:14][CH2:13][C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[CH2:10][CH2:7][OH:8]
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: B
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: OCCc1ccccc1CO
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 69.1 %

Procedure:
Borane-tetrahydrofuran complex (1M solution in tetrahydrofuran, 100 mL) was added dropwise over 10 minutes, to a solution of 2-carboxymethyl-benzoic acid (6 g) in dry tetrahydrofuran (100 mL) at 0° C., under nitrogen. The resulting mixture was stirred at 0-5° C. for 20 minutes, then warmed to room temperature for 1 hour. Saturated citric acid solution (150 mL) was added and the reaction concentrated to ˜150 mL. The aqueous phase was extracted with ethyl acetate (3×150 mL). The combined organics were washed sequentially with 1M aqueous sodium hydroxide solution (150 mL), water (150 mL), brine (150 mL), dried (sodium sulfate) and evaporated to give the subtitle compound as yellow oil (3.5 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[C:50]([C:54](O)=[O:55])=[N:51][O:52][N:53]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:50]2[C:49]([CH3:48])=[N:53][O:52][N:51]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1nonc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nonc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 4-methyl-1,2,5-oxadiazole-3-carboxylic acid as starting materials in 44% yield. LCMS for C28H29ClN9O3 (M+H)+: m/z=574.2.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([C:27](=[O:29])[NH2:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[CH3:32])C=CC=CC=1.CS(C)=O.[CH3:38][NH2:39].O1CCCC1>C(OCC)(=O)C.O>[C:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:30][CH3:31])[N:20]=[CH:19][CH:18]=[C:17]2[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:39][CH3:38])=[O:7])=[C:11]([CH3:32])[CH:12]=1)(=[O:29])[NH2:28]
Reactant: CN
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(C)c3)c2cc1C(N)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(N)=O)cc23)cc1C
Reaction time: 0.08 h

Procedure:
[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-methylphenyl]carbamic acid phenyl ester (70 mg) was added to dimethylsulfoxide (0.8 ml), and then a methylamine-containing 2N tetrahydrofuran solution (0.4 ml) was added and the mixture was stirred for 5 minutes. Water and ethyl acetate were added to the reaction solution, and the precipitated crystals were filtered out to obtain the title compound (48 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([O:17]N3C(=O)CCC3=O)=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=[O:4].[CH3:25][O:26][CH2:27][C:28]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH:36]([NH2:40])[CH2:35][CH2:34]2)([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:40][CH:36]3[C:37]4[C:33](=[CH:32][C:31]([C:28]([CH3:30])([CH3:29])[CH2:27][O:26][CH3:25])=[CH:39][CH:38]=4)[CH2:34][CH2:35]3)=[O:17])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=[O:4]
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: COCC(C)(C)c1ccc2c(c1)CCC2N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCC(C)(C)c1ccc2c(c1)CCC2NC(=O)Nc1cccc2c1cnn2C(=O)OC
Yield: 55 %

Procedure:
4-(2,5-dioxo-pyrrolidin-1-yloxycarbonylamino)-indazole-1-carboxylic acid methyl ester (0.66 g, 2.00 mmol) was added to a solution of 5-(2-methoxy-1,1-dimethyl-ethyl)-indan-1-ylamine (0.46 g, 2.1 mmol) and diisopropylethylamine (0.26 g, 2.00 mmol) in DMF (6 mL) under nitrogen atmosphere at ambient temperature. After 30 minutes the mixture was diluted with water (6 mL). The resulting precipitate was filtered off, washed with aqueous MeCN twice and dried to obtain desired product (0.48 g, 55%). NMR (DMSO-d6): 8.82 (s, 1H), 8.40 (s, 1H), 7.95 (s, 1H), 7.88 (d, J 7.5 Hz, 1H), 7.69 (d, J 8 Hz, 1H), 7.52 (t, J 8 Hz, 1H), 7.24 (m, 2H), 6.70 (d, J 7.5 Hz, 1H), 5.18 (m, 1H), 4.02 (m, 3H), 3.38 (s, 2H), 3.20 (s, 3H), 3.10-2.72 (m, 2H), 2.42 (m, 1H), 1.83 (m, 1H), 1.14 (s, 6H). MS (DCI): 437 (M+1).
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:15]1([C@H:21]2CCC[C@H:22]2[NH2:26])[CH2:20][CH2:19][CH2:18]CC1>>[ClH:1].[CH:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:22]2[CH2:21][CH2:15][CH2:20][CH2:19][CH2:18][NH:26]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N[C@@H]1CCC[C@@H]1C1CCCCC1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Product: C1CCNC(=N[C@@H]2CCC[C@@H]2C2CCCCC2)CC1

Procedure:
By the procedure of Example 1 only employing a reaction time of 29 days and substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of cis-2-cyclohexylcyclopentylamine hydrochloride, the desired product was obtained, M.P. 179°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2cccc(F)c2)cc1
Yield: 85.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.059 g (85%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:21])[C@@H:17]([NH2:20])[CH2:18][OH:19].CCN(CC)CC.[CH3:29][C:30]([Si:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:20][C@H:17]([C@H:16]([OH:21])[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:18][O:19][Si:33]([C:30]([CH3:32])([CH3:31])[CH3:29])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCC=C[C@@H](O)[C@@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 4 h
Yield: 40.1 %

Procedure:
To a solution of D-erythro-sphingosine (46 mg, 0.153 mmol) in CH2Cl2 (1.5 mL) at room temperature, Et3N (32 μL, 0.230 mmol), TBDPSCl (44 μL, 0.169 mmol) and 4-DMAP (ca. 5 mg, cat.) were added. After stirring for 4 h, the reaction was quenched with H2O (10 mL), extracted with EtOAc (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography on silica (hexane/EtOAc 5:1 to 100% EtOAc) to obtain 136 as a colorless oil (33 mg, 40% yield).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C([Sn](CCCC)(CCCC)[C:39]1[O:40][CH:41]=[CH:42][N:43]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:20]([C:4]2[C:5](=[O:19])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=3)[C:7]([CH3:8])=[C:2]([C:39]3[O:40][CH:41]=[CH:42][N:43]=3)[CH:3]=2)=[O:21])=[CH:29][CH:28]=1)(=[O:31])=[O:32]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1c(-c2ncco2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide (0.10 g, 0.169 mmol), 2-tributylstannyl-oxazole (0.12 g, 0.33 mmol, prepared according to literature procedures), Pd(PPh3)4 (0.015 g, 0.012 mmol) and dimethoxyethane (DME, 2.5 ml) and a magnetic stirrer bar were placed in a vial. The suspension was degassed and the vial sealed, and subsequently heated (100° C.) with stirring for 4 h. LC-MS confirmed the conversion of the iodide to the desired product, and the solvents were removed in vacuo. Purification on preparative HPLC afforded the title compound (0.06 g, 67%) as a white solid after freeze-drying the pure fractions.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:14])[N:5]([C:7]2[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)[N:6]=1.[CH3:15][NH2:16]>CC(O)C>[NH2:14][C:4]1[N:5]([C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:16][CH3:15])[CH:12]=2)[N:6]=[C:2]([CH3:1])[CH:3]=1
Reactant: CN
Reactant: Cc1cc(N)n(-c2cc(Cl)ncn2)n1
Solvent: CC(C)O
Product: CNc1cc(-n2nc(C)cc2N)ncn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
5-Methyl-2-(6-chloro-pyrimidin-4-yl)-2H-pyrazol-3-ylamine (2.09 g, 10 mmol) was mixed with methyl amine (40% in water, 9 mL) and 2-propanol (30 mL). The mixture was heated at 50° C. in a sealed tube. After 4 h, the reaction mixture was cooled to room temperature and condensed, triturated with water, and filtered. The solid was washed with water, air-dried to give [6-(5-amino-3-methyl-pyrazol-1-yl)-pyrimidin-4-yl]-methyl-amine (2.08 g, Yield 97%): 1H NMR 400 MHz (d6-DMSO) δ 8.80 (s, 1H), 7.44 (s, 1H), 6.82-6.74 (m, 3H), 5.19 (s, 1H), 2.83 (s, 3H), 2.06 (s, 3H); MS m/z 210.64 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>O1CCOCC1>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N+:15]([O-:27])=[CH:14][C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cnccc21
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1ccc2c[n+]([O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A 100 mL round-bottomed flask was charged with a solution of 1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridine (0.6 g, 2.3 mmol) in dioxane (20 mL). To the resultant solution was added mCPBA (0.6 g, 3.45 mmol) and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo then the residue was dissolved in DCM (50 mL), and washed successively with aqueous sodium sulfite solution, aqueous sodium bicarbonate solution and brine. The organic layer was isolated then dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (0.6 g, 95%). 1HNMR (DMSO, 300 MHz): δ 8.61 (dd, J=1.8, 0.7 Hz, 1 H); 8.13 (dd, J=7.2, 1.8 Hz, 1 H); 8.09-8.04 (m, 2 H); 8.01 (d, J=3.7 Hz, 1 H); 7.92 (d, J=7.2 Hz, 1 H); 7.80-7.73 (m, 1 H); 7.69-7.61 (m, 2 H); 6.83 (dd, J=3.7, 0.8 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.NC(N)=[S:15]>C(O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([SH:15])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH3:12]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: NC(N)=S
Solvent: CCO
Product: CCc1cc(S)n2nccc2n1

Procedure:
5.0 g (27.5 mmol) of the chloride from Example 1, Step B and 4.2 g (55.2 mmol) thiourea were heated in 100 ml dry ethanol for 5 h. The solvent was distilled off in vacuo and the residue crystallized from ethanol/water to give the title compound in yellow crystals, m.p. 178°-180° C.
Reaction SMILES: [Br-].[F:2][C:3]([F:8])([F:7])[C:4]([Zn+])=[CH2:5].[Br:9][C:10]1[C:11]([O:17][CH:18]([F:20])[F:19])=[C:12](I)[CH:13]=[CH:14][CH:15]=1>O1CCCC1.Cl>[Br:9][C:10]1[C:11]([O:17][CH:18]([F:20])[F:19])=[C:12]([C:4]([C:3]([F:8])([F:7])[F:2])=[CH2:5])[CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)Oc1c(Br)cccc1I
Reactant: C=C([Zn+])C(F)(F)F
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1OC(F)F)C(F)(F)F

Procedure:
In 10 ml of a solution of 1-trifluoromethylethenyl zinc bromide prepared according to the method described in documents in 1M tetrahydrofuran, 1.0 g of 3-bromodifluoromethoxy-1-iodobenzene and 0.05 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under reflux with heat for 2 hours. After the completion of the reaction, the reaction mixture was poured in 20 ml of diluted hydrochloric acid, extracted with ethyl acetate (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in hexane, and high polar impurities were excluded by treating with silica gel to obtain 0.77 g of crude aimed product as colorless oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: Cl[C:2]1[C:3]2[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][CH2:13][C:4]=2[N:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)O1>>[CH:8]1([C:6]2[N:7]=[C:2]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=3)[C:3]3[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][CH2:13][C:4]=3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=S1(=O)CCCc2nc(C3CCCC3)nc(Cl)c21
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)Cc1ccc(Cc2nc(C3CCCC3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 45.9 %

Procedure:
Following general procedure H, 4-chloro-2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (0.150 g, 0.52 mmol) was reacted with methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.152 g, 0.52 mmol) to afford the title compound (0.099 g, 46%) as a light yellow oil. MW=414.52. 1H NMR (CDCl3, 500 MHz) δ 7.45 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 4.50 (s, 2H), 3.67 (s, 3H), 3.58 (s, 2H), 3.44-3.40 (m, 2H), 3.27 (quin, J=8.0 Hz, 1H), 3.06 (t, J=6.2 Hz, 2H), 2.48-2.42 (m, 2H), 2.04-1.97 (m, 2H), 1.88-1.73 (m, 4H), 1.70-1.62 (m, 2H); APCI MS m/z 415 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[C:12]2[CH2:13][CH2:14][O:15][C:11]=2[C:10]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[S:21][CH:22]=2)=[CH:9][CH:8]=1)C.[Li+].[OH-]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[S:21][CH:22]=[C:18]([CH2:17][O:16][C:10]3[C:11]4[O:15][CH2:14][CH2:13][C:12]=4[C:7]([CH2:6][CH:5]([O:30][CH2:31][CH3:32])[C:4]([OH:33])=[O:3])=[CH:8][CH:9]=3)[N:19]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)c2c1CCO2)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)c2c1CCO2)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-{7-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2,3-dihydro-benzofuran-4-yl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{7-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2,3-dihydro-benzofuran-4-yl}-2-ethoxy-propionic acid as colorless oil.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26]C(C)(C)[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cu](C#N)[C:32]#[N:33].CC(N(C)C)=O>O>[OH:24][C@H:23]([CH2:27][OH:26])[CH2:22][O:21][C:19]1[CH:18]=[CH:17][C:9]2[C:10]([CH3:15])([CH3:16])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[C:7](=[O:30])[C:8]=2[CH:20]=1)=[CH:4][CH:3]=[C:2]([C:32]#[N:33])[CH:14]=4
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1(C)c2ccc(OC[C@H](O)CO)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Yield: 21.5 %

Procedure:
3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 49.5 mg, 0.105 mmol) and copper cyanide (90%, 35.3 mg, 3.4 eq.) were added with DMA (0.5 mL), and the mixture was irradiated with microwave at 200° C. for 1 hr under nitrogen atmosphere. After cooling, the reaction solution was added with water and extracted with ethyl acetate. The insoluble matters were separated off by filtration, and the organic layer was washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting residues were purified by preparative TLC (methanol/dichloromethane) to obtain the title compound (white solid, 8.5 mg, 22%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:17]2([C:23]([O-:25])=[O:24])[CH2:21][CH2:20][C:19](=[O:22])[O:18]2)[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[C:28]([O:34][CH2:35]Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].O>CN(C=O)C>[O:1]([CH2:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:17]2([C:23]([O:25][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:24])[CH2:21][CH2:20][C:19](=[O:22])[O:18]2)[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COc1ccccc1)N[C@H]1CON(C2(C(=O)[O-])CCC(=O)O2)C1=O
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCOC(=O)C1(N2OC[C@H](NC(=O)COc3ccccc3)C2=O)CCC(=O)O1

Procedure:
Compound (28b) was dissolved in DMF, and chloromethyl pivalate was added to the solution, followed by stirring. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was concentrated, and hexane was added to the residue. The mixture was subjected to decantation twice and to further decantation (twice) with petroleum benzine. The residue was dried through a vacuum pump to give the subject Compound (28c).
Reaction SMILES: [N+:1]([C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:5]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:5]=1[NH:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: COc1cc(F)c([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(F)c(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl 4-[(2-nitro-3-fluoro-5-methoxyphenyl)amino]-piperidine-carboxylate (D12) (380 mg, 1 mmol) was dissolved in ethanol (10 ml) and Raney nickel (50% aqueous suspension, 1 ml) was added at room temperature; the mixture was heated to 40° C. and hydrazine monohydrate (0.5 ml) was added over dropwise. After 30 min more, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent evaporated. The product was purified by silica gel chromatography eluting with 20 to 50% ethyl acetate in hexane to yield the title compound, 250 mg. M+−H=340.