Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[C:56](Cl)(=[O:58])[CH3:57]>>[C:56]([N:26]1[C@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=3[CH3:21])=[CH:12][CH:13]=2)[C:5]([OH:4])=[O:55])=[O:24])[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:43][CH:44]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27]1)(=[O:58])[CH3:57]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was acylated with acetyl chloride according to General Procedure F. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 781.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].O.[ClH:16]>[Pt]>[CH2:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C@H:2]([NH2:1])[C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1.[ClH:16]
Reactant: [H][H]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Pt]
Agent: Cl
Solvent: O
Product: N[C@@H](CC1CCCCC1)C(=O)O
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of 10.4 g (61.7 mmoles) of L-phenylalanine in 150 ml of 2N aqueous hydrochloric acid was subjected to a medium pressure catalytic hydrogenation reaction in the presence of 1 g of platinum black using a Paar's apparatus under about 4 atmospheres of hydrogen at room temperature for 24 hours. At the end of this time, the precipitated crystalline substance was dissolved by adding 250 ml of water, and the catalyst was removed by filtration. The filtrate was then concentrated to about 150 ml by evaporation under reduced pressure and allowed to stand overnight. The crystalline substance which deposited was collected by filtration and dried to give 12.8 g (yield 91%) of the title compound as white crystals, melting at 232°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7](=[O:30])[C@H:8]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:9]=[C:10]([C:11]3[CH:21]=[CH:20][C:14]4[NH:15][C:16](=[O:19])[N:17]([CH3:18])[C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1.ClC1C=CC=CC=1C[C@@H](C(O)=O)N>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7](=[O:30])[C@@H:8]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:9]=[C:10]([C:11]3[CH:21]=[CH:20][C:14]4[NH:15][C:16](=[O:19])[N:17]([CH3:18])[C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1
Reactant: Cn1c(=O)[nH]c2ccc(C3=N[C@@H](Cc4ccccc4Cl)C(=O)Nc4ccc(Cl)cc43)cc21
Agent: N[C@@H](Cc1ccccc1Cl)C(=O)O
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)[nH]c2ccc(C3=N[C@H](Cc4ccccc4Cl)C(=O)Nc4ccc(Cl)cc43)cc21

Procedure:
The following compounds were prepared based on the above general procedures: For example, compound (S)-7-chloro-3-(2-chlorobenzyl)-5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (IV-2) was prepared by using (S)-2-chlorophenylalanine in place of (R)-2-chlorophenylalanineL Optical rotation data: C=1.0 (CHCl3), [α]D=−62°; MS (m/z): 465.1, 467.1; 1H NMR (d6-DMSO) δ 11.08 (s, 1H), 10.75 (s, 1H), 7.63 (m, 1H), 7.53 (m, 1H), 7.40 (m, 1H), 7.33-7.23 (m, 4H), 7.13 (m, 1H), 6.96 (m, 1H), 6.89 (m, 1H) 3.76 (m, 1H), 3.56-3.42 (m, 2H), 3.26 (s, 1H);
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>P(Cl)(Cl)(Cl)=O>[F:1][C:2]([F:14])([F:13])[C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1
Reactant: O=C(NCc1cnccn1)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ncc2cnccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
2,2,2-Trifluoro-N-pyrazin-2-ylmethyl-acetamide 1i (21.0 g, 100 mmol) was added into a reaction flask at room temperature, followed by addition of 100 mL of phosphorus oxychloride. After stirring at room temperature for 30 minutes, phosphorous pentoxide (17.8 g, 125 mmol) was added to the solution. The reaction mixture was heated to reflux for 5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. Phosphorus oxychloride was removed, and the reaction system was quenched with deionized water. The mixture was adjusted to pH 5-6 with 20% sodium hydroxide solution in an ice-water bath. The mixture was extracted with ethyl acetate (250 mL×4), and the combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 3-trifluoromethyl-imidazo[1,5-a]pyrazine 1j (12.0 g, yield 65%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13]C)[CH:8]=1)=[O:5].Br.O>C(O)(=O)C>[F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: COc1cc(NC(=O)c2cc(F)ccc2F)ccn1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)ccc1F
Temperature: 90 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To 2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (2.60 g, 9.84 mmol) in acetic acid (15.60 mL) was added HBr 33% in acetic acid (12.1 mL of 33% w/v, 49.20 mmol) and the mixture was stirred at 90° C. for 5 h. Additional HBr (10 mL, 33% in acetic acid) was added and the mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature and was poured into water (200 mL). The mixture was stirred and the solid was collected by filtration. The solid was washed with water (2×50 mL). The solid was slurried in hexanes (2×50 mL) and filtered to give 2,5-difluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (2.30 g, 9.19 mmol, 93%). ESI-MS m/z calc. 250.05. found 251.3 (M+1)+; Retention time: 1.16 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 10.59 (s, 1H), 7.56 (ddd, J=8.2, 5.4, 3.0 Hz, 1H), 7.46 (pd, J=9.1, 4.4 Hz, 2H), 7.33 (d, J=7.2 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.42 (dd, J=7.2, 2.1 Hz, 1H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[N:12]=[C:11]([C:19]3[CH:20]=[C:21]([C:24]([NH2:26])=[O:25])[S:22][CH:23]=3)[C:5]=2[C:6]([O:9]C)=[N:7][CH:8]=1)#[N:2].[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[N:12]=[C:11]([C:19]3[CH:20]=[C:21]([C:24]([NH2:26])=[O:25])[S:22][CH:23]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2]
Reactant: COc1ncc(C#N)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1c[nH]c(=O)c2c(-c3csc(C(N)=O)c3)nn(C3CCCC3)c12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of 4-(7-cyano-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (53.3 mg) in acetonitrile (10 mL) were added sodium iodide (43.5 mg) and chloro(trimethyl)silane (0.147 mL), and the mixture was stirred at 60° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was washed successively with water and ethyl acetate to give the title compound (50.3 mg).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](O)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:20])=O>CN(C)C=O>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([Cl:20])=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (25.0 g, 103 mmol) in thionyl chloride (22.5 mL, 309 mmol) was added N,N-dimethylformamide (200 μL). The reaction mixture was stirred at room temperature for 2 h. Excess thionyl chloride and N, N-dimethylformamide were removed in vacuo to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (26.3 g, 83%)
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]2[CH2:9][N:10]([C@H:12]3[CH2:17][S:16][CH:15]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])[C@@H:14]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:13]3)[CH2:11][C:5]=12)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:4]1[NH:8][N:7]=[C:6]2[CH2:9][N:10]([C@H:12]3[CH2:17][S:16][CH:15]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])[C@@H:14]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:13]3)[CH2:11][C:5]=12)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3n[nH]c(C(N)=O)c3C2)CSC1c1cc(F)ccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3n[nH]c(C#N)c3C2)CSC1c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
To a stirred solution of tert-butyl N-[(3S,5R)-5-(3-carbamoyl-4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)-2-(2,5-difluorophenyl)tetrahydrothiopyran-3-yl]carbamate (35 mg, 0.073 mmol) in pyridine (4 mL) was added phosphorous oxychloride (0.020 mL, 0.219 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 5.5 h, quenched with water (0.2 mL) and the solvents were removed under vacuum. The residue was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium hydrogen carbonate (1×150 mL), brine, dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by prep-TLC, eluting with 8% MeOH (1N NH3 in MeOH) in CH2Cl2, to give the title compound. MS: 462.1
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:24][CH:23]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1-c1c(Cl)cnn1C
Yield: 15 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-trifluoromethylphenyl isocyanate in a similar manner as described in Example 1.53, providing 8 mg (15%) of Compound 80 (Note: Compound 80 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=427 (M+H37Cl, 22), 425 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.48 (s, 1H), 8.24 (s, 1H), 7.56 (d, J=8 Hz, 2H), 7.50 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.28 (d, J=4 Hz, 1H), 7.27 (s, 1H), 6.96 (d, J=12 Hz, 1H), 3.62 (s, 3H), 3.46 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[CH3:33])[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:27]1([C:25]([NH:24][C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]4[CH:30]=[CH:31][C:32]([CH3:33])=[C:11]([NH:10][C:7]([C:5]5[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:12]=4)=[N:20][N:19]3[CH:21]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)[nH]n1
Yield: 71 %

Procedure:
In the same manner as in Example 261 and using 3-methyl-1H-pyrazole-5-carboxylic acid (160 mg, 1.2 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), 1-hydroxybenzotriazole (170 mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.2 mmol), triethylamine (190 mg, 1.9 mmol) and N,N-dimethylformamide (3 mL) as starting materials, the title compound (190 mg, 70%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:47]=[CH:46][C:35]([C:36]([NH:38][C:39]2[C:40]([NH2:45])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:37])=[CH:34][CH:33]=1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:45][C:40]2[C:39]([NH:38][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:47][CH:46]=3)=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:14])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: CC(C)(C)OC(=O)NCCCOc1cc(OCc2ccccc2)ccc1C(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OCc3ccccc3)cc2OCCCNC(=O)OC(C)(C)C)cc1
Yield: 65.7 %

Procedure:
In a manner substantially equivalent to Example 101-D, 4-benzyloxy-2-(3-tert-butoxycarbonylaminopropoxy)benzoic acid (4.98 g, 12.4 mmol) and N1-(4-methoxybenzoyl)-1,2-benzenediamine (3.00 g, 12.4 mmol) were coupled to give 5.10 g (65.7%) of the title compound as a white foam after purification by silica gel (hexanes:EtOAc) chromatography on a Waters prep 500 instrument.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]2[C:29]=1[CH:30]([C:44]1[C:52]([OH:53])=[CH:51][C:47]3[O:48][CH2:49][O:50][C:46]=3[CH:45]=1)[C:31](=[O:43])[N:32]2[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[Cl:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]2[C:29]=1[C:30]([C:44]1[C:52]([OH:53])=[CH:51][C:47]3[O:48][CH2:49][O:50][C:46]=3[CH:45]=1)([CH2:5][OH:16])[C:31](=[O:43])[N:32]2[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (94%) as a gummy solid: MS (ES+) m/z 439.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:5][N:6]=1.[C:15](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:20])[CH2:16][C:17]([O-])=[O:18]>C1(C)C(C)=CC=CC=1>[CH:9]1([CH2:8][CH2:7][C:4]2[S:3][C:2]3=[N:1][C:15]([OH:20])=[CH:16][C:17](=[O:18])[N:6]3[N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C([O-])CC(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1nnc(CCC2CCCCC2)s1
Solvent: Cc1ccccc1C
Product: O=c1cc(O)nc2sc(CCC3CCCCC3)nn12
Yield: 82 %

Procedure:
2-Amino-5-(2-cyclohexylethyl)-[1,3,4]thiadiazole (9.50 g) and 21.8 g of 2,4,6-trichlorophenyl malonate were stirred in 70 ml of xylene at a bath temperature of from 140° to 150° C. for 2 hours. After cooling, the precipitate formed was collected by filtration and washed successively with ethanol and diethyl ether to obtain 10.3 g of 2-(2-cyclohexylethyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a colorless plate-like crystal.
Reaction SMILES: C(O[CH:4]([O:36]CC)[CH2:5][CH:6]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)[OH:8])C.S(=O)(=O)(O)O.O.[OH-].[Na+]>O1CCCC1>[OH:36][CH:4]1[O:8][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][CH:14]=2)[CH:6]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:5]1
Reactant: CCOC(CC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCN2CCOCC2)cc1)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1CC(c2ccccc2)C(c2ccccc2)(c2ccc(OCCN3CCOCC3)cc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The evaporation residue obtained in step (a) is dissolved in a mixture containing 19.5 g of concentrated sulfuric acid, 150 ml of water and 400 ml of tetrahydrofuran. The mixture is stirred for 3 h at room temperature. The solution is neutralized with 2M sodium hydroxide solution and the solvent is evaporated. The product is extracted in toluene containing ethyl acetate. The solution is dried over sodium sulfate. The solvent is evaporated, and the residue is recrystallized from toluene. The yield is 12.0 g (27% from desoxybenzoin) of a product having m.p. 150°-3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH2:22][O:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([CH3:32])[CH:25]=3)=[C:12]([CH2:14][O:15]C3CCCCO3)[N:13]=2)=[CH:5][CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:15][CH2:14][C:12]1[N:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][C:11]=1[CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([CH3:32])[CH:25]=1
Reactant: COc1ccc(-c2nc(COC3CCCCO3)c(COc3ccc(C#N)c(C)c3)o2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc(CO)c(COc3ccc(C#N)c(C)c3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
5.96 g 4-[2-(4-Methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-5-ylmethoxy]-2-methyl-benzonitrile were dissolved in 100 ml methanol. 522 mg p-toluenesulfonic acid monohydrate were added and the reaction mixture stirred at room temperature for one hour. The solvent was removed in vacuo. The residue was dissolved in 150 ml ethyl acetate and washed with 80 ml saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4 and the solvent was evaporated in vacuo to obtain 4.1 g 4-[4-hydroxymethyl-2-(4-methoxy-phenyl)-oxazol-5-ylmethoxy]-2-methyl-benzonitrile as pale yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>CO>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][CH:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: C=CCN1CCN(c2ccc(N)nc2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
300 mg (1.21 mmol) of 1-allyl-4-(6-nitropyridin-3-yl)piperazine from Example 15.1 were dissolved in 20 ml of methanol, after which 2.18 g (9.67 mmol) of tin(II) chloride dihydrate were added and the mixture was stirred at 70° C. for 2 hours. After the solvent had been evaporated down to dryness, the resulting residue was treated with water and this mixture was made alkaline using a dilute aqueous solution of sodium hydroxide and extracted with ethyl acetate. The solid which had precipitated out was filtered off with suction. The phases were then separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated down to dryness, with 183 mg (69% of theory) of the title compound being obtained.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:9]([C:17]2[CH:18]=[C:19]3[CH:25]=[CH:24][NH:23][C:20]3=[CH:21][N:22]=2)=[CH:8]1)(C)(C)C.[C:26]([O:30]N=C1C2C(=CC=CC=2)OC(C2C=C3C=CN(O)C3=CN=2)=C1)(C)(C)C.[H-].[Na+].IC>CN(C)C=O.[Cl-].[Na+].O.ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:26][O:30][N:23]1[C:20]2=[CH:21][N:22]=[C:17]([C:9]3[O:10][C:11]4[C:16]([C:7](=[N:6][OH:5])[CH:8]=3)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:18]=[C:19]2[CH:25]=[CH:24]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cc[nH]c3cn2)oc2ccccc12
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccn(O)c3cn2)oc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COn1ccc2cc(-c3cc(=NO)c4ccccc4o3)ncc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 70/30 mixture of 2-(1H-Pyrrolo[2,3-c]pyridin-5-yl)-chromen-4-one O-tert-butyl-oxime and 2-(1-Hydroxy-1H-pyrrolo[2,3-c]pyridin-5-yl)-chromen-4-one O-tert-butyl-oxime (77 mg) in dimethylformamide (5 ml) was cooled to 0° C. and treated with sodium hydride (60% in mineral oil, 10 mg, 0.25 mmol) and stirred at room temperature for 1 hour. The solution was cooled down to 0° C. and treated with iodomethane (16 μl, 0.25 mmol). The solution was slowly warmed up to room temperature during 1 hour and poured into brine, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated to dryness. The crude mixture of 2-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-chromen-4-one O-tert-butyl-oxime and 2-(1-methoxy-1H-pyrrolo[2,3-c]pyridin-5-yl)-chromen-4-one O-tert-butyl-oxime was treated with titanium tetrachloride (0.70 mmol) in dichloromethane (7.5 ml) (method D) to yield separately after purification by preparative HPLC (gradient 65-50% Water/Methanol+0.05% trifluoroacetic acid), 2-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-chromen-4-one oxime (example 77, 17 mg) and 2-(1-methoxy-1H-pyrrolo[2,3-c]pyridin-5-yl)-chromen-4-one oxime (example 78, 12 mg) as yellow solids.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:9]([N:16]1[CH:20]=[C:19]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:18]=[N:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Brc1ccc(-c2cnn(Cc3ccccc3)c2)cc1
Yield: 99.4 %

Procedure:
4-Bromo-iodobenzene (240 mg, 0.8 mmol, 1.2 eq.), 1-benzylpyrazole-4-boronic acid pinacol ester (200 mg, 0.7 mmol), potassium acetate (70 mg, 1 eq.), Pd(dppf)Cl2 (70 mg, 0.1 eq.), and Cs2CO3 (700 mg, 3.0 eq.) in DMSO (5 mL) were heated under argon at 80° C. during 1 h. The reaction mixture was extracted from water into diethyl ether, dried over Na2SO4, concentrated, and chromatographed on silica gel (5→10% EtOAc/hexanes) to give 1-benzyl-4-(4-bromophenyl)pyrazole (218 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:33].[C:34]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([F:33])=[C:2]([NH:1][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(N)cc2n1Cc1ccccc1
Reactant: O=C1CCCC1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(NC3CCCC3)cc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172) and cyclopentanone by General Procedure T.