Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[CH3:6][O-].[Na+].[Cl:9][C:10]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([C:30](OCC)=[O:31])[N:14]2C>CO>[Cl:9][C:10]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([C:30]([N:4]=[C:3]([NH2:5])[NH:2][CH3:6])=[O:31])[NH:14]2
Reactant: C[O-]
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc2c(Cl)cc(Oc3ccccc3[N+](=O)[O-])cc2n1C
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(Cl)cc(Oc3ccccc3[N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
After 2.87 g (30.0 mmol) of guanidine hydrochloride was added to 25 ml of a methanol solution of 1.62 g (30.0 mmol) of sodium methoxide, the mixture was stirred at room temperature for 30 minutes. The precipitated sodium chloride was filtered off. To the obtained solution was added 0.51 g (1.50 mmol) of ethyl 4-chloro-1-methyl-6-(2-nitrophenoxy)-2-indolecarboxylate. Subsequently methanol was distilled off under reduced pressure. The resulting residue was heated at 130° C. for 5 minutes and then allowed to stand at room temperature for an hour. Thereafter water was poured onto the reaction solution and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography to give 0.23 g (40.1%) of 4-chloro-1-methyl-6-(2-nitrophenoxy)-2-indoloylguanidine.
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[CH2:3][C:4]([O-:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[CH:57][CH:56]=3)[N:49]=2)=[CH:44][CH:43]=1>CN(C=O)C>[OH:1][C@@H:2]([CH3:7])[CH2:3][C:4]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([N:61]4[CH2:62][CH2:63][O:64][CH2:65][CH2:66]4)=[CH:59][CH:60]=3)[N:49]=2)=[CH:44][CH:43]=1)=[O:6]
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Reactant: C[C@H](O)CC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](O)CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of (S)-3-hydroxybutyrate (0.180 g, 1.73 mmol), HATU (0.602 g, 1.58 mmol), DIEA (1.0 mL, 5.4 mmol) in DMF (3.0 mL) was added a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine (0.500 g, 1.44 mmol) in DMF (1.0 mL). The reaction mixture was stirred at rt for 2 hours, at which time it was quenched with saturated NaHCO3 (10 mL, aq.), extracted into DCM (3×), and washed with brine (1×). The organic layers were dried with sodium sulfate and concentrated. The product was purified by reverse phase HPLC to afford (S)-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)butanamide (0.136 g, 22% yield) as a light brown solid. (363) 1H-NMR (400 MHz, DMSO-d6): 10.14 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 4.79 (d, 1H), 4.11 (m, 1H), 3.74 (m, 4H), 3.05 (m, 4H), 2.47 (dd, 1H), 2.35 (dd, 1H)), 1.15 (d, 3H); MS (EI) m/z for C24H28N5O3: 434.3 (MH+).
Reaction SMILES: [CH2:1]1[CH:7]([OH:8])[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[CH2:16]([O:23][C:24](=[O:27])[NH:25]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClC(Cl)(Cl)C(O)=O>C(Cl)Cl>[CH2:16]([O:23][C:24](=[O:27])[NH:25][O:8][CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NO)OCc1ccccc1
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(NOC1CCOP(=O)(N(CCCl)CCCl)N1)OCc1ccccc1
Reaction time: 72 h

Procedure:
750 mg (2.7 mmol) of 4-hydroxycyclophosphamide and 450 mg (2.7 mmol) of benzyl-hydroxycarbamate are dissolved in 6 ml of methylene chloride free of alcohol. A small amount of trichloroacetic acid is added thereto and the solution is allowed to stand at -25° C. in a refrigerator for 3 days. The resulting solution is filtered off, the mother liquor is diluted with 5 ml of chloroform, then is diluted with water and thereafter is washed with a dilute solution of NaHCO3 and with water. The washed solution is dried over sodium sulfate and is evaporated in a vacuum. The oily residue thereafter is recrystallized from acetic acid ethyl ester containing a small amount of methanol.
Reaction SMILES: O[CH:2]([NH:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:11]=1)=[O:9])[C:3](Cl)([Cl:5])[Cl:4]>C(O)(=O)C.C(OCC)(=O)C.O.[Zn]>[Cl:5][C:3]([Cl:4])=[CH:2][NH:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=2)[N:11]=1)=[O:9]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC(O)C(Cl)(Cl)Cl)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC=C(Cl)Cl)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
1.0 g (0.0022 mol) of N-(1-hydroxy-2,2,2-trichloroethyl)-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide was dissolved in about 10 ml of acetic acid. The obtained solution was mixed with 0.29 g (0.0022×2.0 mol) of zinc dust and stirred at about 50° C. for about 5 hours. The reaction solution was distributed in ethyl acetate-water and washed with saturated sodium bicarbonate water and saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[NH2:23])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.CCOC(C)=O>C1COCC1>[O:11]=[C:10]1[NH:23][C:16]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=2[NH:14][CH2:13][C@@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: Cc1cc(C)c(N)c(NC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(C)c2c(c1)NC[C@H](NC(=O)OC(C)(C)C)C(=O)N2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A 0° C. solution of (2S) -2-tert-butoxycarbonylamino-3-(2-amino-3,5-dimethylphenyl-amino)-propionic acid (763 mg, 2.36 mmol) and N-methylmorpholine (483 mg, 4.78 mmol) in 60 ml of anhydrous THF was treated dropwise with isobutylchloroformate (352 mg, 2.5 mmol). The reaction was stirred for 2 h at 0° C., at RT for 1 h and poured over EtOAc. The mixture was washed with aq. 5% NaHSO4, sat. aq. NaHCO3, and sat. aq. NaCl, dried over NaSO4, and concentrated in vacuo. Chromatography (flash, SiO2, 10% to 25% to 50% EtOAc/CH2Cl2) gave 490 mg (68%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br:35][C:36]1[C:41](I)=[CH:40][CH:39]=[CH:38][N:37]=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:41]5[C:36]([Br:35])=[N:37][CH:38]=[CH:39][CH:40]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Brc1ncccc1I
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5Br)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-bromo-3-iodo-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.15 min; Mass spectrum (ESI+): m/z=498/500 (Br) [M+H]+.
Reaction SMILES: [NH:1]([C:8](=[O:33])[CH2:9][N:10]1[C:18]2[CH:17]=[CH:16][C:15]([Cl:19])=[C:14]([Cl:20])[C:13]=2[C:12]2[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:11]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:19].[Cl:19][C:15]1[CH:16]=[CH:17][C:18]2[N:10]([CH2:9][C:8]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:33])[C:11]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:12]=3[C:13]=2[C:14]=1[Cl:20]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)Nc3ccccc3)c3ccc(Cl)c(Cl)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(Cn1c2c(c3c(Cl)c(Cl)ccc31)CCNCC2)Nc1ccccc1
Temperature: 25 °C
Reaction time: 69 h
Yield: 132.1 %

Procedure:
To a solution of tert-butyl 6-(2-anilino-2-oxoethyl)-9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (40 mg, 0.082 mmol) in CH2Cl2 (3 mL), TFA (0.032 mL, 0.41 mmol) was added while stirring at rt. Additional TFA (0.032 mL, 0.41 mmol) was added after 3 h. After 69 h, TFA (0.25 mL, 3.2 mmol) was added along with additional CH2Cl2 (3 mL). The reaction was quenched with 10% aqueous NaOH (5 mL) after 70 h and extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to give 30 mg of crude solid. The hydrochloride salt prepared to give 23 mg (67%) of a white solid: mp 274.0-276.0° C.; 1H NMR (300 MHz, DMSO) δ 7.58 (d, J=7.9 Hz, 2H), 7.52 (d, J=8.7 Hz, 1H), 7.32 (m, 3H), 7.07 (t, J=7.2 Hz, 1H), 5.14 (s, 2H), 3.56 (m, 2H), 3.18 (m, 2H); IR (diffuse reflectance) 2995, 2983, 2967, 2948, 2940, 2936, 2809, 2767, 1680, 1600, 1549, 1448, 1314, 797, 759 cm−1; MS (ES+) m/z 388 (M+H+), 361, 359, 268, 266, 242, 241, 240, 238, 228, 226; Anal. Calcd for C20H19Cl2N3O.HCl: C, 56.55; H, 4.75; N, 9.89; found: C, 56.25; H, 4.89; N, 9.50.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[CH:25]=[C:24]2[CH:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)#[N:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.Cl>ClC(Cl)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([C@@H:34]4[CH2:33][CH2:32][C@H:31]([C:24]5[C:23]6[C:27](=[CH:28][CH:29]=[C:21]([C:19]#[N:20])[CH:22]=6)[N:26]([CH3:30])[CH:25]=5)[CH2:36][CH2:35]4)[CH2:17][CH2:18]3)[N:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc2cccnc2c(N2CCNCC2)n1
Reactant: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COc1cc2cccnc2c(N2CCN([C@H]3CC[C@@H](c4cn(C)c5ccc(C#N)cc54)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-methoxy-8-piperazin-1-yl-[1,7]naphthyridine (250 mg, 1.02 mmol), 4-(5-cyano-1-methyl-1H-indol-3-yl)-cyclohexanone (260 mg, 1.02 mmol), and sodium triacetoxyborohydride (320 mg, 1.53 mmol) in dichloroethane (50 mL) was added acetic acid (0.12 mL, 2.04 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) then extracted in CH2Cl2 (1×50 mL) and EtOAc (75 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and chromatographed (5% MeOH/EtOAc+NH4OH) affording 160 mg (33%) of the cis isomer as a yellow foam. The HCl salt was generated form EtOAc affording a pale yellow solid: mp 235-238° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][NH:11][CH2:12][CH2:13][C:14]2[NH:15][C:16]3[C:21]([C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:9][CH2:8]1.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C(O)C.CCCCC>[Cl:29][CH2:30][C:31]([N:11]([CH2:10][CH:7]1[CH2:9][CH2:8]1)[CH2:12][CH2:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:32]
Reactant: c1ccc(-c2c(CCNCC3CC3)[nH]c3ccccc23)cc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: CCCCC
Product: O=C(CCl)N(CCc1[nH]c2ccccc2c1-c1ccccc1)CC1CC1

Procedure:
3-Phenyl-1H-indol-2-ethanamine are reacted with cyclopropanecarboxylic acid chloride to give N-cyclopropylcarbonyl-3-phenyl-1H-indol-2-ethanamine, which is reduced with lithium aluminium hydride to N-cyclopropylmethyl-3-phenyl-1H-indol-2-ethanamine, which is reacted with chloracetyl chloride to give 2-chloro-N-cyclopropylmethyl-N-[2-(3-phenyl1H-indol-2-yl)ethyl]acetamide, m.p. 104°-106° (from ethanol/pentane).
Reaction SMILES: [Na].Br[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(OCC)C.[Cl-].[Na+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:3]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: C=CCCCC(C(=O)OCC)C(=O)OCC
Reaction time: 2 h
Yield: 58.2 %

Procedure:
7.05 g of sodium were dissolved in a solution of 40 g of diethyl malonate in 175 ml of ethanol. The still warm solution (50° C.) was treated dropwise within 15 minutes with 45.6 g of 5-bromo-1-pentene and the mixture was heated to boiling for 2 hours. After cooling the reaction mixture was poured into 500 ml of diethyl ether and 300 ml of semi-saturated sodium chloride solution. The aqueous phase was separated and back-extracted twice with 200 ml of diethyl ether each time. The organic phases were washed twice with 150 ml of semi-saturated sodium chloride solution each time dried over sodium sulphate, filtered and concentrated. Chromatographic separation of the resulting, yellow liquid (55.2 g) on silica gel with hexane/ethyl acetate (vol. 95:5) gave 33.2 g of diethyl (4-pentenyl)malonate as a colourless liquid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1C(O)=O.[CH:29]([N:32]1CCNCC1)(C)[CH3:30]>>[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:7]2[C:2]([NH:32][CH2:29][CH2:30][N:28]3[CH2:20][CH2:21][CH2:25][CH2:26][CH2:27]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[CH2:11][CH2:12]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCN(C(=O)c2cccnc2Cl)CC1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1cccnc1Cl
Product: CC(C)N1CCN(C(=O)c2cccnc2NCCN2CCCCC2)CC1

Procedure:
(2-Chloro-pyridin-3-yl)-(4-isopropyl-piperazin-1-yl)-methanone. The title compound was prepared in a manner similar to that described in Step A of Example 9 using 2-chloro-nicotinic acid and 1-isopropyl-piperazine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[C:20]#[CH:21]>O1CCCC1>[C:24]([O:23][C:19](=[O:22])[C:20]#[C:21][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cccc(I)c1
Reactant: C#CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C#CC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
To the mixture of methyl 3-iodobenzoate (157 mg, 0.60 mmol), potassium carbonate (166 mg, 1.20 mmol), cupper(I) iodide (14 mg, 0.07 mmol) and PdCl2(Ph3P)2 (21 mg, 0.03 mmol) in tetrahydrofuran (2 mL) was added tert-butyl propiolate (330 μL, 2.40 mmol) at room temperature. After stirred for 20 h at 60° C., the mixture was evaporated to dryness. The residue was chromatographed on a silica gel (EtOAc:hexanes=0:1˜1:10) to give the title compound 9-1 (155 mg, 99% yield) as a light brown oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])(=[O:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:18]=[C:17]([CH2:19][Br:20])[CH:16]=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cc(C)ccc1C(=O)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(CBr)ccc1C(=O)c1ccccc1
Yield: 63.4 %

Procedure:
A mixture comprising 1.3 g of the 2-acetoxy-4-methylbenzophenone prepared in the step (c), 910 mg of N-bromosuccinimide and 20 ml of carbon tetrachloride was heated under reflux together with a small amount of benzoyl peroxide for one hour. The reaction mixture was cooled and filtered through a silica gel bed, and the silica gel was washed with 20% ethyl acetate/hexane. The filtrate and washings were concentrated together. The residue was subjected to silica gel column chromatography (7 to 10% ethyl acetate/hexane) to give 1.08 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[C:5]([CH3:11])[C:3]=1[NH2:4].[F:12][B-:13]([F:16])([F:15])[F:14].[H+].[N:18]([O-])=O.[Na+]>O>[F:12][B-:13]([F:16])([F:15])[F:14].[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[C:5]([CH3:11])[C:3]=1[N+:4]#[N:18]
Reactant: O=N[O-]
Reactant: Cc1cc(F)c(C)c(F)c1N
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)c(C)c(F)c1[N+]#N

Procedure:
To 2,4-difluoro-3,6-dimethylaniline (3.1 g) are added 42% tetrafluoroboric acid (9 ml) and water (4.5 ml) with stirring and under ice-cooling, followed by dropwise addition of a solution of sodium nitrite (1.6 g) in water (3.2 ml) below 10° C. After stirring the mixture at 0° C. for 15 minutes, the resulting crystals are filtered, washed with a mixture of ethanol-diethyl ether (1:2) and then with diethyl ether, followed by drying under reduced pressure to give 2,4-difluoro-3,6-dimethylbenzene diazonium tetrafluoroborate (1.78 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([F:16])[CH:6]=2.C[CH2:19][N:20](C(C)C)[CH:21]([CH3:23])[CH3:22].CNC(C)C>CS(C)=O>[F:16][C:7]1[CH:6]=[C:5]2[C:10]([N:11]=[C:2]([N:20]([CH3:19])[CH:21]([CH3:23])[CH3:22])[C:3](=[O:17])[NH:4]2)=[CH:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc2nc(Cl)c(=O)[nH]c2cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CNC(C)C
Solvent: CS(C)=O
Product: COC(=O)c1cc2nc(N(C)C(C)C)c(=O)[nH]c2cc1F
Temperature: 85 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of methyl 3-chloro-7-fluoro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (2.0 g, crude) in DMSO (20 ml) was added DIEA (2.0 g, 15.48 mmol) and methyl(propan-2-yl)amine (790 mg, 10.80 mmol) with stirring at 85° C. overnight. The reaction mixture was cooled to room temperature. The product was precipitated by the addition water and the solids were collected by filtration to afford methyl 7-fluoro-3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (800 mg).
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[CH2:15]([OH:20])[C:16]#[C:17][CH2:18][OH:19].C(N(CC)CC)C>ClCCCl.C[C]1[C](C)[C](C)[C](C)[C]1C.C1CC=CCCC=C1.Cl[Ru]>[CH3:12][O:11][C:9]([C@H:6]1[CH2:7][CH2:8][C@H:3]([C:2]2[C:17]([CH2:18][OH:19])=[C:16]([CH2:15][OH:20])[O:14][N:13]=2)[CH2:4][CH2:5]1)=[O:10]
Reactant: OCC#CCO
Reactant: COC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Agent: Cl[Ru]
Agent: C1=C\CC/C=C\CC/1
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1=CCCC=CCC1
Product: COC(=O)[C@H]1CC[C@H](c2noc(CO)c2CO)CC1
Reaction time: 20 h

Procedure:
To a mixture of trans-methyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (0.900 g, 4.10 mmol) and but-2-yne-1,4-diol (0.370 g, 4.30 mmol) in 1,2-dichloroethane (41.0 ml) was added chloro(1,5-cyclooctadiene)(pentamethylcyclopentadienyl)ruthenium(II) (0.0778 g, 205 μmol) and triethylamine (0.713 ml, 5.12 mmol) at room temperature. The reaction mixture was stirred for 20 h. The solvent was evaporated. The residue was triturated in ethyl acetate (50 ml). The solids were removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.758 g, 69%) as light brown oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[C:10]([O:15]C)[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3]1.B(Br)(Br)Br.O.O.NN>C(Cl)Cl>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([OH:15])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccc(Cl)cc2)c2cc(SC)c(OC)cc2S(=O)(=O)C1
Agent: BrB(Br)Br
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CCCCC1(CCCC)CN(c2ccc(Cl)cc2)c2cc(SC)c(O)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
To a solution of 1,1-dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 98; 0.26 g 0.52 mmol) in anhydrous DCM (10 ml) was added boron tribromide (2.63 g, 10.48 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 2.5 h. The reaction flask was cooled to 0° C., water (20 ml) and hydrazine monohydrate (0.5 ml) was added. The organic layer was separated, dried and evaporated under reduced pressure. The crude product was purified by column chromatography using DCM/EtOAc (100:5 and 100:10) as eluent to give the title compound 0.20 g (80%). NMR (500 MHz) 0.85 (t, 6H), 1.03–1.28 (m, 8H), 1.35–1.46 (m, 4H), 2.39 (s, 3H), 3.21 (s, 2H), 3.73 (s, 2H), 7.04 (d, 2H), 7.29–7.34 (m, 3H), 7.44 (s, 1H); m/z 482.
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.CN(C)C=O.[Cl:18][C:19]1[C:20]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:21]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:22]2=[N:23][C:24]=1[CH2:25]Cl>O>[Cl:18][C:19]1[C:20]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:21]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:22]2=[N:23][C:24]=1[CH2:25][N:6]1[C:2](=[O:12])[C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7]
Reactant: COc1ccc(-c2c(Cl)c(CCl)nc3sc4c(c23)CCSC4)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)c4ccccc4C3=O)nc3sc4c(c23)CCSC4)cc1
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a mixture of phthalimide potassium (6.2 kg) and dimethylformamide (110.74 L) was added 3-chloro-2-chloromethyl-5,8-dihydro-4-(4-methoxyphenyl)-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridine (11.055 kg) obtained in Reference Example 27 and the mixture was stirred at 60 to 65° C. for 1 hour. After cooling to 25° C., water (36.91 L) was added dropwise thereto and the mixture was stirred at the same temperature for 1 hour. The crystals deposited was filtered off and washed with water (29. 14 L) to obtain the titled compound (14.057 kg, 99.4%). 1H-NMR (CDCl3) δ: 2.14 (2H, t, J=5.7 Hz), 2.64 (2H, t, J=5.7 Hz), 3.80 (2H, s), 3.89 (3H, s), 5.20 (2H, s), 6.98-7.13 (2H, s), 6.98-7.13 (3H, m), 7.75-7.78 (2H. m), 7.79-7.794 (2H, m).