Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:13][C:3]1[CH:4]=[C:5]([S:8]([NH:11][CH3:12])(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CNS(=O)(=O)c1ccc(Cl)c(N)c1
Temperature: 90 °C
Yield: 100.3 %

Procedure:
A solution of 4-chloro-N-methyl-3-nitrobenzenesulfonamide (6.35 g, 25.3 mmol) in EtOH (150 mL) and water (50.0 mL) was treated with iron (14.15 g, 253 mmol) and NH4Cl (13.55 g, 253 mmol) and heated at 90° C. for 4 hours before being cooled and filtered through celite. The filter cake was washed with EtOAc and the combined filtrate was filtered again to remove precipitated NH4Cl before being concentrated. The resulting crude material was partitioned between 350 ml EtOAc and 50 ml saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, concentrated and subjected to flash column chromatography (330 g silica gel, 0-15% EtOAc/DCM) to afford 3-amino-4-chloro-N-methylbenzenesulfonamide (5.60 g, 100%) as a light yellow crystalline solid. 1H NMR (400 MHz, MeOD) δ ppm 7.39 (d, J=8.28 Hz, 1 H), 7.27 (d, J=2.26 Hz, 1 H), 7.03 (dd, J=8.28, 2.26 Hz, 1 H), 2.54 (s, 3 H). MS 221.0 (M+H+).
Reaction SMILES: CC([O:5][C:6](=[O:18])[CH2:7][S:8][C:9]1[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][CH:10]=1)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:15]([NH:14][C:12]1[S:13][C:9]([S:8][CH2:7][C:6]([OH:18])=[O:5])=[CH:10][N:11]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1ncc(SCC(=O)OC(C)(C)C)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ncc(SCC(=O)O)s1
Yield: 97 %

Procedure:
A solution of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid 1,1-dimethylethyl ester (4.32 g, 15 mmol) in methylene chloride (30 mL) and trifluoroacetic acid (20 mL) was stirred at rt overnight and concentrated in vacuo. To the residue was added ethyl ether (50 mL). The precipitated solid was collected, washed with ethyl ether and dried to afford the desired product (3.38 g, 97%) as a solid, mp 210° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].NC1C(Cl)=CC2NC(N3C=[C:39]([C:41](O)=[O:42])C=N3)=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)(=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][C:41](=[O:42])[CH3:39])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)Cl
Product: CCOC(=O)c1cnn(-c2nc3cc(NC(C)=O)c(Cl)cc3n2COCCOC)c1
Reaction time: 3 h
Yield: 81 %

Procedure:
To a stirred suspension of 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.300 g, 0.762 mmol) and THF (4 mL) was added diisopropylethylamine (0.330 mL, 1.90 mmol) at 0° C. Acetyl chloride (57.0 μL, 0.800 mmol) was then added. After 3 h, the reaction was quenched with water (10 mL) and extracted with EtOAc (3×35 mL). The combined organic layers were washed with brine (15 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-65% EtOAc/hexanes) to yield the titled compound (0.270 g, 81%) as a 2:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C19H22ClN5O5, 435.1; m/z found, 436.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.83 (s, 1H), 8.71 (s, 1H), 8.18 (s, 1H), 7.79 (br s, 1H), 7.74 (s, 1H), 6.10 (s, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.66-3.62 (m, 2H), 3.48-3.43 (m, 2H), 3.29 (s, 3H), 2.29 (s, 3H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH2:20][CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH:24]=2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([F:18])[CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([F:18])[CH:9]=2)=[N:6][C:5]([C:19]2[CH2:20][CH2:21][CH2:22][NH:23][CH:24]=2)=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2nc(C3=CN(C(=O)OC(C)(C)C)CCC3)cnc2N)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(C3=CNCCC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
To tert-butyl 5-(5-amino-6-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (150 mg, 0.350 mmol) (inseparable mixture) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred at room temperature for 30-45 min. The reaction mixture was evaporated on rotovap, and azeotroped with toluene. The crude product was proceeded to next step without purification. LCMS (m/z): 329.2 (MH+), 0.502 min.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:15]([N:18]=C=O)(=[O:17])=[O:16].[Cl-].[Cl-].[Cl-].[Al+3]>[N+](CC)([O-])=O>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:13][C:12]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: Nc1ccc(C2CCCCC2)cc1S(N)(=O)=O
Temperature: 0 °C
Yield: 31 %

Procedure:
A solution of 4-cyclohexylaniline (0.877 g, 5.0 mmol, 1.0 eq) in nitroethane (5 mL) was cooled to −40° C., treated dropwise with chlorosulfonyl isocyanate (0.87 g, (0.523 mL, 6.15 mmol, 1.23 eq), warmed to 0° C., treated with aluminum trichloride (0.85 g, 6.35 mmol, 1.27 eq), heated in a 110° C. oil bath for 30 minutes, cooled to ambient temperature, and poured into 200 mL of ice water. The mixture was filtered and the filter cake was rinsed with cold water, dissolved in 50% H2SO4 (25 mL), heated to reflux for 4 hours, cooled to ambient temperature, poured into 200 mL of ice water, and carefully neutralized to pH 7 with 40% NaOH. The reaction mixture was extracted with ethyl acetate (3×100 mL) and the combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to give 0.40 g of the desired product (31% yield). MS (ESI+) m/z 255.0 (M+H)+, 272.1 (M+H2O)+, 277.0 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) δ 1.32 (m 4H), 1.71 (m, 6H), 2.36 (m, 1H), 5.64 (s, 2H), 6.72 (d, J=8.09 Hz, 1H), 7.11 (dd, J=8.46, 2.21 Hz, 1H), 7.16 (s, 2H), 7.38 (d, J=2.21 Hz, 1H).
Reaction SMILES: C([O:5][C:6](=[O:69])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](=[O:68])[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]([C:61]([O:63]C(C)(C)C)=[O:62])[NH:40][C:41](=[O:60])[NH:42][C@H:43]([C:53]([O:55]C(C)(C)C)=[O:54])[CH2:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O>[C:6]([CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](=[O:68])[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([C:61]([OH:63])=[O:62])[NH:40][C:41](=[O:60])[NH:42][CH:43]([C:53]([OH:55])=[O:54])[CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH2:15][C:16]([OH:18])=[O:17])([OH:69])=[O:5]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCCCCCN(CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)CCCCCCCCCCN(CC(=O)O)Cc1nccn1CC(=O)O)C(=O)O)C(=O)O

Procedure:
A solution of (19 S,23S)-tetra-tert-butyl 2-((1-(2-tert-butoxy -2-oxoethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylate (18.8 mg, 0.019 mmol) in TFA (1.0 mL)/DCM (1.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to give 19S,23S)-2-((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid as a colorless oil. To a solution of the above deprotected product in water (1.0 mL) that was adjusted to pH=9 by 2 N NaOH was added Re(CO)3(H2O)OTf (0.50 mL, 0.10 mL/mmol). The reaction mixtures were stirred at room temperature for overnight and purified by HPLC to afford the title compound (4.0 mg, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.70 (t, J=5.6 Hz, 1H), 7.33 (s, 1 H), 7.13 (s, 2 H), 6.29 (d, J=8.4 Hz, 1 H), 6.26 (d, J=8.4 Hz, 1H), 4.96 (d, J=4.8 Hz, 2 H), 4.56 (d, J=16.4 Hz, 1 H), 4.12 (d, J=16.8 Hz, 1 H), 4.07-3.90 (m, 2 H), 3.70 (d, J=17.2 Hz, 1 H), 3.40 (d, J=17.2 Hz, 1 H), 2.98-2.94 (m, 4 H), 2.21 (q, J=7.73, 2 H), 1.99 (t, J=7.6 Hz, 2 H), 1.70-1.22 (m, 24 H); MS (ESI), 485.2 (M/2+H)+.
Reaction SMILES: O[CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH3:18])[CH:12]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]1=[O:39])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].N1C=CC=CC=1.S(Cl)([Cl:48])=O>O1CCCC1.O1CCOCC1>[Cl:48][CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH3:18])[CH:12]([NH:19][C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:11]1=[O:39])[C:3]([O:5][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC#CCSC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1C(O)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC#CCSC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1C(Cl)C(=O)OC(C)(C)C

Procedure:
1-(1-Hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one (0.44g) was dissolved in a 1:1 mixture of dry tetrahydrofuran and dioxan (10ml) and the solution, under nitrogen, was cooled to -10°. Pyridine (0.2g) in dry dioxan (2.5ml) was added, followed by the dropwise addition of thionyl chloride (0.19ml) in dioxan (2.5ml) over 2-3 minutes. After a further 15 minutes the precipitated solid was filtered off and the filtrate evaporated to dryness. Dry toluene was added to the residue and decanted off from any solid. The organic solution was evaporated to dryness and re-evaporation from dry ether gave 1-(1-chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one as an amorphous solid (0.45g).
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[C:23]([C:27]1[CH:67]=[CH:66][C:30]([C:31]([NH:33][C@@H:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([NH:48][NH:49][C:50](=O)[C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[CH:53][CH:52]=3)=O)=[CH:42][CH:41]=2)[C:35]([O:37][CH3:38])=[O:36])=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([C:27]1[CH:67]=[CH:66][C:30]([C:31]([NH:33][C@@H:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]3[S:10][C:50]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[CH:53][CH:52]=4)=[N:49][N:48]=3)=[CH:42][CH:41]=2)[C:35]([O:37][CH3:38])=[O:36])=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2nnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)s2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
Prepared using INT-3: To a stirring solution of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (65.7 mg, 0.16 mmol) in THF (3 mL) was added (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoate INT-3 (100.0 mg, 0.16 mmol) and the mixture heated to 65° C. After 1 h, the reaction mixture was concentrated and purified by column chromatography (10-100% EA in iso-hexanes) to afford 37.0 mg (29%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazol-2-yl)phenyl)propanoate as a yellow solid. LCMS-ESI (m/z) calculated for C36H43N3O4S: 613.8; no ion observed, tR=3.31 min. (Method 4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.NC1C=CC(S(C(=C)C#N)(=O)=O)=CC=1.S(=O)(=O)(O)O.C(N(CC)CC)C.[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>CN(C)C=O.O>[CH3:52][C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)(=[O:50])=[O:49])=[CH:44][CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)C=CS(=O)(=O)c1ccc(N)cc1
Agent: C=C(C#N)S(=O)(=O)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC(N)=O)cc2)cc1
Reaction time: 16 h

Procedure:
22.6 g (0.1 mol) of 3-(4-aminobenzenesulfonyl)acrylamide, prepared by hydrolysis of 3-(4-aminobenzenesulfonyl acrylonitrile with a 1:1 molar mixture of concentrated sulfuric acid and water, is dissolved in dimethylformamide (100 ml), and 14.5 ml triethylamine (0.1 mol) are added thereto. A solution of p-toluenesulfonyl chloride (19.1 g, 0.1 mol) in 50 ml dimethylformamide is added dropwise at room temperature, and the reaction mixture is left undisturbed for 16 hours. The product is recovered by precipitation with water and recrystallization from ethanol. There is thus produced 3-[4-(4-methylbenzenesulfonamido)benzenesulfonyl]acrylamide: ##SPC14##
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[C:61](B(O)O)[CH:60]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]3)=[CH:7][CH:8]=2)[C:3](=[O:32])[C:2]=1[C:61]1[CH:60]=[N:59][C:68]2[C:63]([CH:62]=1)=[CH:64][CH:65]=[CH:66][CH:67]=2
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2ccc(F)cc2F)CC1
Yield: 71 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 of Example 116 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-quinolinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (71%).
Reaction SMILES: O.[CH2:2]([NH2:6])[CH2:3][CH2:4][CH3:5].[C:7](OCC)(=[O:10])[C:8]#[CH:9].[Na+].[Cl-]>C(O)(=O)C>[CH2:2]([NH:6][C:7](=[O:10])[C:8]#[CH:9])[CH2:3][CH2:4][CH3:5]
Reactant: C#CC(=O)OCC
Reactant: CCCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C#CC(=O)NCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 30 mL of water and 7.68 g (105 mmol) n-Butylamine is added dropwise 9.8 g (100 mmol) ethyl propiolate at 0° C. for 30 minutes. The mixture was stirred for 2 h at 0° C., then acetic acid (2 mL) was added. The mixture was stirred for another 10 minutes and saturated with NaCl, followed by extraction with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated aqueous solution of NaHCO3 (20 mL), dried over Na2SO4, and removed by rotary evaporation to give product (12.0 g, yield 95%, purity 69% by GC).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1.[CH3:26][NH:27][C:28](=O)[O:29]C1C=CC=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[NH2:25][C:21]1[CH:20]=[C:19]([O:18][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[O:8][CH2:7][CH2:6][CH2:5][O:4][CH3:3])[N:15]([C:28]([NH:27][CH3:26])=[O:29])[CH:14]=[CH:13]3)[CH:24]=[CH:23][N:22]=1
Reactant: CNC(=O)Oc1ccccc1
Reactant: COCCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)c(OCCCOC)cc21
Reaction time: 0.17 h
Yield: 93 %

Procedure:
50-72% Oily sodium hydride (308 mg) was added to a solution of 4-((6-(3-methoxypropoxy)-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 32-7 (2.23 g, 7.12 mmol) in N,N-dimethylformamide (30 mL) under nitrogen atmosphere at 0° C. The reaction liquid was stirred for 10 minutes, then phenyl methylcarbamate described in Production Example 1-7 (1.40 g, 9.25 mmol) was added, and the resultant was further stirred at the same temperature for 30 minutes. Water and ethyl acetate were added to the reaction liquid. The organic layer was washed serially with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=9:1-0:1) to obtain the title compound (2.44 g, 93%).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:13][N:12]=2)=[C:7]([Cl:35])[CH:6]=1.[Li+].[OH-].Cl.C(Cl)Cl>C1COCC1.O>[Cl:35][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[C:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:14]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:13][N:12]=1
Reactant: COC(=O)Cc1ccc(-c2noc(-c3ccccc3)c2COCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(-c2noc(-c3ccccc3)c2COCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(3-Chloro-4-{4-[2-(2,4-dichloro-phenoxy)-ethoxymethyl]-5-phenyl-isoxazol-3-yl}-phenyl)-acetic acid methyl ester 41 (0.75 mmol) is dissolved in THF (5 mL). A solution of 1 M LiOH in H2O (3.5 mL) is added and the mixture is stirred for 6 hours at room temperature. The mixture is acidified with 1 M HCl (3 mL), DCM (50 mL) is added and the organic layer washed with H2O (2×30 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound H2 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.84 (m, 2H), 7.44-7.19 (m, 7H), 7.06 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 4.45 (s, 2H), 4.00 (t, J=4.5 Hz, 2H), 3.71 (t, J=4.5 Hz, 2H), 3.62 (s, 2H). MS calculated for C26H21Cl3NO5 (M+H+) 532.0, found 532.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([S:12][CH3:13])[C:3]=1[CH3:14].[CH3:15][C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17].[H-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:8])[CH2:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])=[C:4]([S:12][CH3:13])[C:3]=1[CH3:14]
Reactant: COC(=O)c1ccc(Cl)c(C)c1SC
Reactant: CC(=O)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1c(C(=O)CC(=O)C2CC2)ccc(Cl)c1C
Yield: 84.5 %

Procedure:
A mixture of methyl 4-chloro-3-methyl-2-(methylsulphenyl)benzoate (19.5 g) and cyclopropyl methyl ketone (13.4 g) in dry tetrahydrofuran was added to a stirred heated suspension of sodium hydride (80% oil dispersion, 4.8 g) in dry tetrahydrofuran. The mixture was stirred and heated at reflux for 2 hours. It was cooled and hydrochloric acid (2 ml) was added. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with water, saturated aqueous sodium bicarbonate, water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 1-(4-chloro-3-methyl-2-methylsulphenylphenyl)-3-cyclopropylpropan-1,3-dione (20.19 g) as a yellow oil, NMR(CDCl3) 0.9(m,2H), 1.2 (m,2H), 1.7(m,1H), 2.3(s,3H), 2.65(s,3H), 5,85 (s,1H), 7.15(d,1H), 7.3(d,1H), 15.7-16.0(bs,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:14](=O)[CH:15]([CH3:17])[CH3:16])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:19][NH2:20].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>C(O)C>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH3:16][CH:15]([C:14]1[C:11]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=3[C:26]([C:25]3[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=3)=[N:13][C:12]=2[NH:20][N:19]=1)[CH3:17]
Reactant: NN
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccc(C(C#N)C(=O)C(C)C)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc2c(-c3ccc(O)cc3)nc3[nH]nc(C(C)C)c3c2cc1OC
Temperature: 70 °C
Yield: 33 %

Procedure:
2-[3,4-bis(methyloxy)phenyl]-4-methyl-3-oxopentanenitrile (100 mg, 0.40 mmol) was dissolved in ethanol (1 mL), and anhydrous hydrazine (98%, 16 μL, 0.52 mmol) was added. The resulting mixture was heated at reflux for 1 hour. It was cooled, concentrated, and the residue was dried in vacuum for one hour. To this residue was added of 4-hydroxybenzaldehyde (74 mg, 0.61 mmol) and trifluoroacetic acid (1 mL), and the mixture was heated at 70° C. for 18 hours. Then the reaction mixture was concentrated, dissolved in 10 mL of N,N-dimethylformamide and purified by preparatory HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic eluent). After concentration and lyophillization of the pure fractions 4-[1-(1-methylethyl)-7,8-bis(methyloxy)-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetic acid salt (60 mg, 0.13 mmol, 33% yield) was obtained. 1H NMR (400 MHz, d6-DMSO): 7.62-7.60 (d, 2H), 7.58 (s, 1H), 7.55 (s, 1H), 6.98-6.96 (d, 2H), 4.04 (s, 3H), 3.77-3.75 (m, 1H), 3.76 (s, 3H), 1.49-1.46 (d, 2H); MS (EI) for C21H21N3O3: 363 (MH+).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH2:17][CH3:18])[S:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:26]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH2:17][CH3:18])[S:3]1)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CC(=O)Cl
Reactant: CCc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)CC(C)C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a solution of 2-imino-3-(3-trifluoromethylphenyl)-5-ethylthiazoline (0.5 g) and triethylamine (0.6 g) in chloroform (30 ml), isovaleryl chloride (0.8 g) was dropwise added under stirring at room temperature, and stirring was continued for 2 hours. After removal of the solvent under reduced pressure, the concentrated residue was extracted with ethyl acetate (100 ml), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.2 g of 2-isovalerylimino-3-(3-trifluoromethylphenyl)-5-ethylthiazoline (Compound No. 16).