Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([NH:8][CH:9]1[C:19]2[C:20]3[C:12](=[C:13]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[NH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10]1)=[O:7])([O-])=O.C(OCC)(=O)C>CO.[C].[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([NH:8][CH:9]1[C:19]2[C:20]3[C:12](=[C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58 %

Procedure:
A portion (250 mg) of the compound obtained in Example 128 was suspended in methanol (50 ml) and to the suspension was added 10% palladium-carbon (25 mg). The mixture was stirred for 3.5 hours at room temperature under a hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was crystallized from ether to yield 134 mg (58%) of the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[N:8][C:9]2[CH:21]=[CH:20][CH:19]=[N:18][C:10]1=2
Reactant: c1cnc2c(c1)N=C(c1ccncc1)c1ccccc1N2
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2ccncc2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(4-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([Cl:15])=[C:7]([O:16][CH3:17])[N:6]=1.O>C(O)CC>[Cl:15][C:8]1[C:7]([O:16][CH3:17])=[N:6][C:5]([NH:2][NH2:3])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=1
Reactant: NN
Reactant: COc1nc(Cl)c(C(F)(F)F)cc1Cl
Solvent: O
Solvent: CCCO
Product: COc1nc(NN)c(C(F)(F)F)cc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
10.7 g (0.214 mol) of hydrazine hydrate were added at 50° C. in the course of 10 minutes with stirring to 25.0 g (0.102 mol) of 2,5-dichloro-6-methoxy-3-trifluoromethylpyridine in 100 ml of propanol and the mixture was stirred for 3 hours at 90° C. After cooling, the resulting suspension was poured into 1.2 liters of water, and the precipitate was filtered off with suction, taken up in methylene chloride and washed with water. The organic phase was dried and concentrated, and the residue was stirred with ether/pentane (1:1). After filtration with suction and drying, 7.8 g (32% of theory) of the title compound of m.p. 140°-142° C. (Table II, No. 2.011) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18]C)=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[CH:7]=1.B(Br)(Br)Br.CO.O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Oc1ccc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
2-(5-chloro-2-methoxyphenyl)-4-fluoro-1H-indole (50 mg, 0.2 mmol) was dissolved in dichloromethane (1 mL), and then BBr3 (150 mg, 0.6 mmol) was added at −78° C. The mixture was stirred at −78° C. for 1 hour, and then stirred at 25° C. for 12 hours. MeOH (1 mL) and H2O (20 mL) were added to the solution. The mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=5:1) to provide the product of 4-chloro-2-(4-fluoro-1H-indol-2-yl)phenol (10 mg, yield: 25%). 1H-NMR (CDCl3, 400 MHz) δ 9.54 (s, 1H), 7.65 (s, 1H), 7.06˜7.12 (m, 2H), 6.88 (s, 1H), 6.79˜6.81 (m, 1H), 6.70˜6.74 (m, 1H). MS (M+H)+: 262/263.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].Cl.[NH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50].C(N(CC)CC)C>ClCCl>[CH2:52]([O:51][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][NH:45][S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3])[CH3:53]
Reactant: CCOC(=O)CCCN
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNS(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A mixture of 600 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 394 mg of ethyl 4-aminobutyrate hydrochloride, 0.27 mL of triethylamine, and 6.0 mL of dichloromethane was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 442 mg of methyl 4-{2-[4-({[2-({3-[(4-ethoxy-4-oxobutyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[CH2:39][C:40]([OH:42])=O)=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.CNC.[CH2:46]([NH2:48])[CH3:47]>>[CH2:46]([NH:48][C:40](=[O:42])[CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:29]=[CH:28][C:27]([C:25]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:26])=[CH:32][CH:31]=1)[CH3:47]
Reactant: CCN
Reactant: O=C(O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: CNC
Product: CCNC(=O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Yield: 61 %

Procedure:
The title compound was prepared in essentially the same manner as Example 68, replacing 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylic acid with (4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-yl)acetic acid of Example 35, and dimethylamine with ethylamine. Purification by flash chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane gave the title compound (0.152 g, 61%) as a white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=O)[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:51][CH:52]([NH2:54])[CH3:53].C([BH3-])#N.[Na+]>O1CCCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][NH:54][CH:52]([CH3:53])[CH3:51])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CNC(C)C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reaction time: 2 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-formyl-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (40 mg, 0.058 mmol, 1.0 equiv) was mixed with propan-2-amine (6.90 mg, 0.117 mmol, 2.0 equiv) in Tetrahydrofuran (583 μl) and Methanol (146 μl). The solution was stirred for 2 hours. LCMS show about 50% conversion to imine. Then to this solution was added sodium cyanoborohydride (21.99 mg, 0.350 mmol, 6.0 equiv) and stirred for 2 hours. The mixture was used for next reaction directly. LCMS (ESI, M+1): 729.4.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH2:10][O:9][CH2:8][CH2:7][C:5]=2[N:6]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[N:6]1[C:5]2[CH2:7][CH2:8][O:9][CH2:10][C:4]=2[S:3][CH:2]=1
Reactant: [H][H]
Reactant: Clc1nc2c(s1)COCC2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc2c(s1)COCC2
Yield: 79.7 %

Procedure:
2-Chloro-6,7-dihydro-4H-pyrano[4,3-d]thiazole (1.78 g) was dissolved in methanol (30 ml), and to the solution 10% palladium on carbon (300 mg) and sodium acetate (830 mg) were added. The mixture was stirred for 5 days in a hydrogen stream of 5 atm. After the catalyst was separated by filtration, the filtrate was concentrated, and the residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain 6,7-dihydro-4H-pyrano[4,3-d]thiazole (1.14 g) as a colorless oil.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[N:35]1[CH:37]([C:41]([O:43][CH3:44])=[O:42])[CH2:38][CH2:39][CH2:40][CH:34]1[CH:33]2[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C1(CC2C3C(=C(OC)C=CC=3)N(C(CCC)C(OC)=O)C=2)C=CC=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[N:35]1[CH:37]([C:41]([O:43][CH3:44])=[O:42])[CH2:38][CH2:39][CH2:40][C:34]1=[C:33]2[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)C1CCCC2C(Cc3ccccc3)c3cccc(OC)c3N12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC(C(=O)OC)n1cc(Cc2ccccc2)c2cccc(OC)c21
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C1CCCc2c(Cc3ccccc3)c3cccc(OC)c3n21

Procedure:
A solution of 1.8 gm (4.7 mmol) of the product from Part B and 4 mL (15 mmol) of tri-n-butyltin hydride in 5.0 mL of toluene was heated to reflux and treated dropwise with a solution of 85 mg (0.5 mmol) of 2,2′-azobis(2-methylpropionitrile). The solution was refluxed 1 hour after the addition, cooled, evaporated in vacuo, taken up in ethyl acetate, shaken with aqueous potassium floride, and filtered. The organic phase was washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo to give a mixture of 4-methoxy-6-methoxycarbonyl-10-phenylmethyl-6,7,8,9,9a,10-hexahydropyrido[1,2-a]indole and methyl 2-[3-phenylmethyl-7-methoxyindol-1-yl]pentanoate which was dissolved in 25 mL of dioxane and stirred with 450 mg (2 mmol) of dichlorodicyanoquinone for 30 minutes. The solution was evaporated in vacuo, taken up in dichloromethane, filtered through florisil, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient hexane/10-20% ethyl ether to give the title compound, 75 mg, 5%, as an amorphous solid. 1H NMR (CDCl3) δ: 1.70 (m, 1H), 1.85 (m, 1H), 2.20 (m, 1H), 2.35 (m, 1H), 2.70 (m, 1H), 3.00 (m, 1H), 3.70 (s, 3H), 3.80 (s, 3H), 4.00 (q, 2H), 5.65 (m, 1H), 6.50 (d, 1H), 6.90 (t, 1H), 7.00 (d, 1H), 7.10 (m, 1H), 7.20 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.[CH2:23]1C[O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH:24]=[CH2:23])=[CH:11][CH:10]=2)#[N:13]
Reactant: C1CCOC1
Reactant: COc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(OC)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 500 mg (1.72 mmol) 6-amino-4-[(3-methoxyphenyl)amino]-3-quinolinecarbonitrile in 2 ml hot DMF, added 6 ml THF, and chilled to 0° C. Added 264 μl (1.90 mmol) triethylamine and 158 μl (1.90 mmol) acryloyl chloride. Removed ice bath at 15 minutes. Stripped solvent at 2 hours. Washed residue with dilute sodium bicarbonate, collected solids, washed with water, and air dried. Boiled solids in ethyl acetate, collected and dried in vacuo, giving 288 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=345.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]([CH2:27][C:28]([OH:30])=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ClC(Cl)(Cl)C#N.[NH2:37][C@@:38]([C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][CH2:62][C:63]([F:66])([F:65])[F:64])=[CH:55][CH:54]=1)([C:49]([F:52])([F:51])[F:50])[CH2:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=1)=[O:41].N1C=CC=CC=1>C(Cl)Cl>[O:20]([CH2:27][C:28]([NH:37][C@:38]([C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][CH2:62][C:63]([F:64])([F:65])[F:66])=[CH:55][CH:54]=1)([CH2:39][C:40](=[O:41])[C:42]1[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=1)[C:49]([F:52])([F:51])[F:50])=[O:30])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)COc1ccccc1
Reactant: Cc1ccc(C(=O)C[C@](N)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)C[C@](NC(=O)COc2ccccc2)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
To a mixture of triphenylphosphine (138 mg, 0.318 mmol) in dry DCM (0.8 mL) was added 2-phenoxyacetic acid (26 mg, 0.173 mmol), followed by trichloroacetonitrile (30 mg, 0.208 mmol). The mixture was stirred at rt for 2.5 h. To the mixture was added a solution of Intermediate 2F, isomer 2 (30 mg, 0.069 mmol) in dry DCM (0.5 mL) followed by pyridine (17 μL, 0.208 mmol). The reaction was stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC (MeOH/H2O/TFA) to yield the desired product (27 mg, 69%) as a brown oil. LCMS Anal. Calc'd for C29H27F6NO4 567.18, found [M+H] 568.3.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH2:9][CH:10]([NH2:14])[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[C:18]([O:22][C:23](ON=C(C1C=CC=CC=1)C#N)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[C:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH2:9][CH:10]([NH:14][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CC(=O)c1cccc(OCCC(N)C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(OCCC(NC(=O)OC(C)(C)C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 33.2 %

Procedure:
DL-4-(m-Acetylphenoxy)-2-aminobutyric acid (4.30 g.), 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (4.92 g.) and triethylamine (2.53 g.) were dissolved in a mixture of dioxane (22 ml.) and water (22 ml.), whereafter the mixture was stirred at ambient temperature for 2.5 hours. The dioxane was removed by evaporation from the reaction mixture under reduced pressure to give an aqueous solution which was adjusted to pH 8-9 with an aqueous sodium bicarbonate. The resultant aqueous solution was washed with ethyl acetate and adjusted to pH 2 with 10% hydrochloric acid under ice-cooling. This solution was extracted three times with ethyl acetate, and the extract was washed with water and then dried over magnesium sulfate. The solvent was removed by evaporation from the solution under reduced pressure to give DL-4-(m-acetylphenoxy)-2-tert-butoxycarbonylaminobutyric acid (2.03 g.).
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[C:3]1[CH:8]=[CH:7][C:6]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(O)(=[O:19])C.N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:10][S:9]([F:14])([F:13])([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([C:2]([Cl:1])=[O:19])=[CH:4][CH:5]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C(Cl)(Cl)Cl)cc1
Reactant: CC(=O)O
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(Cl)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 56.1 %

Procedure:
Into a 25 mL flask equipped with a stirrer were placed 10.0 g (31.2 mmol) of the 4-trichloromethyl(pentafluorosulfanylbenzene) prepared in Example 1 and 0.15 g (3 mol %) of FeCl3. To the mixture, 1.87 g (31.2 mmol) of acetic acid was added dropwise at an oil bath temperature of 70° C. in a N2 atmosphere for 3 hours. After the addition was complete, the mixture was heated with stirring at an oil bath temperature of 70° C. for 17 hours. After the mixture was cooled to room temperature, it was mixed with 0.49 g (6 mol %) of triphenylphosphine and was stirred for 3 hours. This mixture was distilled under reduced pressure to yield 4.67 g of 4-pentafluorosulfanylbenzoic chloride (product yield: 56%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH3:13][C@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.CN(C=O)C>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([N:20]3[CH2:19][CH2:18][CH:17]([O:16][CH2:15][C@@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:13])[CH2:22][CH2:21]3)=[N:6][C:5]=2[CH:7]=1
Reactant: COc1ccc2sc(Cl)nc2c1
Reactant: C[C@@H](COC1CCNCC1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2sc(N3CCC(OC[C@H](C)NC(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 64.3 %

Procedure:
A mixture of 2-chloro-5-methoxy-1,3-benzothiazole (143 mg), tert-butyl [(1S)-1-methyl-2-(piperidin-4-yloxy)ethyl]carbamate (186 mg), N,N-diisopropylethylamine (93 mg) and DMF (3 mL) was stirred at 150° C. for 1.5 hr under microwave irradiation. Water was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (194 mg).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([F:34])[C:32]=1[F:33])[NH2:29]>ClCCCl>[CH2:2]([CH:3]([NH:29][C:28]1[CH:27]=[C:26]([F:25])[C:32]([F:33])=[C:31]([F:34])[CH:30]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCC(CC)Nc1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-Pentanone, acetic acid and sodium triacetoxyborohydride were added to a 1,2-dichloroethane solution of 3,4,5-trifluoroaniline, for stirring at ambient temperature for 14 hours, to obtain N-(1-ethylpropyl)-3,4,5-trifluoroaniline.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]3)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.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].C(Cl)Cl>[NH2:11][C:7]1[C:6]2[C:2]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]4)=[CH:3][O:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Nc1nccc2occ(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4ccnc(N)c34)ccc21
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A mixture of 3-bromofuro[3,2-c]pyridin-4-amine (3.002 g, 14.09 mmol), 1,1-dimethylethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (5.346 g, 15.48 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.573 g, 0.702 mmol) in 1,4-Dioxane (120 mL) and saturated aqueous sodium bicarbonate (43 mL, 43.0 mmol) was degassed with Nitrogen for 20 minutes. The mixture was then stirred at reflux under Nitrogen for 16 hours. It was then cooled, poured into half-saturated aqueous NaHCO3 (250 mL), and extracted with ethyl acetate (2×250 mL). The extracts were washed with brine (1×250 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 400 g SiO2, 20%-100% EtOAc in hexanes gradient over 60 minutes, then 100% EtOAc for 15 more minutes) to give 1,1-dimethylethyl 5-(4-aminofuro[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (3.93 g) as an off-white solid. LC/MS (ES) m/z=352 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([NH2:18])=O)=[N:15][N:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1.S(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]#[N:18])=[N:15][N:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: Cn1c2ccc(Cl)cc2c(=O)n2nc(C(N)=O)cc12
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1c2ccc(Cl)cc2c(=O)n2nc(C#N)cc12
Temperature: 56 °C

Procedure:
A mixture of 3.0 g of 7-chloro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide, 1.6 ml of thionyl chloride and 35 ml of dimethylformamide is stirred and heated at 56° C. for 18 hrs, then evaporated at reduced pressure. The residue is stirred with 600 ml of water for 1 hour and the resulting solid 7-chloro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carbonitrile is collected by filtration, washed with water and dried; mp 350° C., after crystallization from dimethylformamide/ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:22])=[C:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][C:3]=1C(O)=O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH3:1][C:2]1[C:6]2[C:7]([OH:22])=[C:8]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1
Reactant: Cc1c(C(=O)O)oc2c(C(=O)c3cccs3)cc(C(C)(C)C)c(O)c12
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Cc1coc2c(C(=O)c3cccs3)cc(C(C)(C)C)c(O)c12
Temperature: 200 °C

Procedure:
To a solution of 3-methyl-4-hydroxy-5-tert-butyl-7-(2-thienoyl)-benzofuran-2-carboxylic acid (0.345 g, 0.96 mmol) in quinoline (1.0 mL) at room temperature was added fine copper powder (0.061 g, 0.96 mmol). The reaction mixture was flushed with nitrogen and heated in an oil bath to 200° C. until all CO2 evolution had ceased (about 20 min.). The reaction mixture was cooled to room temperature and poured into 30 mL 2N HCl. The aqueous solution was extrated with EtOAc (3×15 mL). The combined organic extracts were washed with 2N HCl (2×10 mL), water (10 mL) and saturated NaCl (10 mL) and dried over Na2SO4. Filtration, concentration and flash chromatography (85:15, hexane:EtOAc) afforded pure compound 14. 1H NMR d 1.5 (9H, s), 2.5 (3H, s), 5.74 (1H, s), 7.18 (1H, dd, J=4 Hz), 7.34 (1H, s), 7.68 (1H, d, J=4 Hz), 7.73 (1H, d, J=4 Hz), 7.74 (1H, s).