Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)=[N:8]2.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)=[N:8]3)=[O:36])=[CH:33][CH:32]=1
Reactant: NCc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a cooled (ice bath) and stirred solution of (5-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (100 mg, 0.345 mmol) and triethyl amine (38 mg, 0.38 mmol) in tetrahydrofuran (THF) (2 ml) was added 4-fluorobenzoyl chloride (60 mg, 0.38 mmol) and the mixture was allowed to stir at room temperature for 16 h. Evaporation and purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as white solid (90 mg, 63%). M.p. 145° C.; MS: m/e=412.3 (M+H+).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].[BrH:14].N([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.O.[Cu](Br)Br.[Cu]Br>[Br:14][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Br
Reactant: CC(C)Cc1ccc(N)cc1C#N
Agent: Br[Cu]Br
Agent: [Cu]Br
Agent: O=C([O-])O
Solvent: O
Solvent: CC#N
Product: CC(C)Cc1ccc(Br)cc1C#N
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-2-isobutylbenzonitrile (D57) (34 g) in acetonitrile (500 mL) was added HBr (24.37 mL) at 0° C. Then a solution of sodium nitrite (16.16 g) in water (50 mL) was added to the reaction mixture. After stirring for 30 min, copper(II) bromide (87 g) and copper(I) bromide (5.60 g) were added to the reaction mixture. The mixture was stirred at room temperature for 16 h. Saturated aqueous sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with EA. The combined organic solution was dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography to give 5-bromo-2-(2-methylpropyl)benzonitrile (D58) (36 g) as a colorless oil. 6H (CDCl3, 400 MHz): 0.96 (6H, d), 1.98 (1H, m), 2.69 (2H, d), 7.18 (1H, d), 7.64 (1H, dd), 7.55 (1H, d).
Reaction SMILES: [NH2:1][C@@H:2]([C:10](=[O:25])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]2=[O:24])=[CH:14][CH:13]=1)[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>ClCCl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:1][C@H:2]([CH2:3][P:4]([O:5][CH3:6])([O:7][CH3:8])=[O:9])[C:10]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]3=[O:24])=[CH:16][CH:17]=2)=[O:25])=[CH:29][CH:28]=1
Reactant: COP(=O)(C[C@@H](N)C(=O)Nc1ccc(N2CCOCC2=O)cc1)OC
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COP(=O)(C[C@@H](NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(N2CCOCC2=O)cc1)OC
Yield: 98.8 %

Procedure:
5.4 The solution of 0.2 g (0.54 mmol) of dimethyl (S)-{2-amino-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]ethyl}phosphonate and 0.092 g (0.54 mmol) of 4-chlorophenyl isocyanate in 10 ml of dichloromethane is stirred at room temperature for 12 hours. The methylene chloride solution is subsequently washed successively with 10 ml of each of 1N hydrochloric acid, saturated sodium hydrogencarbonate solution and water and dried over sodium sulfate. After the solvent has been stripped off, 10 ml of diethyl ether are added to the residue, and the white precipitate deposited is filtered off, giving 0.28 g (100%) of (S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(3-oxomorpholin-4-yl)phenyl]-3-(dimethoxyphosphoryl)propionamide (“1D”), ESI 525.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:8]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:4][CH:3]=1.[S:37]1[CH:41]=[C:40]([CH:42]([CH3:46])[C:43](O)=[O:44])[N:39]=[CH:38]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:21]([O:20][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C@@H:9]1[CH2:10][CH2:11][C@H:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:43](=[O:44])[CH:42]([C:40]3[N:39]=[CH:38][S:37][CH:41]=3)[CH3:46])=[CH:36][CH:35]=2)[N:8]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(F)c1
Reactant: CC(C(=O)O)c1cscn1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1ccc(C[C@H]2CC[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)c3cccc(F)c3)N2C(=O)OC(C)(C)C)cc1)c1cscn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50 mg (0.10 mmol) of tert-butyl(5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(3-fluorophenyl)methyl]pyrrolidine-1-carboxylate (i-4c) and 2-(1,3-thiazol-4-yl)propanoic acid (15 mg, 0.10 mmol) in 3 mL anhydrous DMF was added a 0.5 M solution of HOAt in DMF (0.2 mL, 0.10 mmol) followed by EDC (25 mg, 0.15 mmol) and DIEA (16.5 μL, 0.1 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×5 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate (500 uM) eluting with 5% MeOH in dichloromethane to yield the product as a mixture of diastereomers. The two diastereomers were then separated by chiral HPLC employing a Daicel CHIRALPAK® AD® column (eluent: 40% IPA in Heptane). The first eluting diastereomer was designated as Isomer 1 and is a colorless solid. LC-MS: m/z (ES) 655 (MH)+, 677 (MNa)+. The second eluting diastereomer was designated as Isomer 2 and is also a colorless solid. m/z (ES) 654 (MH)+, 676 (MNa)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:27]1[N:28]([CH2:36][CH3:37])[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[N:32][C:31]=12.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]=[C:14]1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:27]2[N:28]([CH2:36][CH3:37])[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][C:31]=23)=[CH:24][CH:23]=1
Reactant: CCn1nc2cccnc2c1Br
Reactant: CC1(C)OB(c2ccc(Oc3nc4ccccc4[nH]3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCn1nc2cccnc2c1-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Yield: 59.1 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazole (116 mg), 3-bromo-2-ethyl-2H-pyrazolo[4,3-b]pyridine (71 mg), tetrakis(triphenylphosphine)palladium(0) (36.3 mg), cesium carbonate (153 mg) and DME/water (3/1, 4 ml) was subjected to microwave irradiation at 120° C. for 40 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound (66.0 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.S(C)C>C1COCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][NH2:7])[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)c1cccc(Br)c1F
Solvent: C1CCOC1
Solvent: CSC
Product: NCc1cccc(Br)c1F
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a solution of 3-bromo-2-fluorobenzamide (3.0 g, 13.76 mmol) in THF (50 mL) was added BH3.Me2S (1.57 mL, 20.6 mmol) and the mixture was stirred at 50° C. for 2 h (monitored by TLC). The reaction was quenched by adding HCl (20 mL, 3 N) after which the result mixture was stirred for 2 h and then THF was removed under vacuum. The aqueous layer was extracted with AcOEt (30 mL), and then was adjusted to pH=9.0 with NaOH (1 N). Then the aqueous layer was extracted with AcOEt (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 1.30 g of the title compound as a colorless oil (yield: 46%). 1H NMR (400 MHz, D2O) δ 4.30 (S, 2H), 7.19-7.22 (m, 1H), 7.47 (t, J=8.8 Hz, 1H), 7.73-7.77 (m, 1H); 13C NMR (100 MHz, D2O) δ 37.4, 108.9, 121.2, 126.2, 130.7, 135.1, 156.2, 158.6.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[N:13]([CH2:14][CH2:15][CH3:16])[N:12]=[CH:11][C:10]=1[C:17]([NH2:19])=[O:18])=O)[CH3:2].[OH-].[Na+]>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]1[NH:19][C:17](=[O:18])[C:10]2[CH:11]=[N:12][N:13]([CH2:14][CH2:15][CH3:16])[C:9]=2[N:8]=1)[CH3:2]
Reactant: CCCn1ncc(C(N)=O)c1NC(=O)c1ccccc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1ncc2c(=O)[nH]c(-c3ccccc3OCC)nc21
Yield: 88.7 %

Procedure:
A solution of 5-(2-ethoxybenzamido)-1-n-propyl-pyrazole-4-carboxamide (Preparation 2; 0.541 g, 0.0017 mol) and sodium hydroxide (0.10 g, g, 0.0026 mol) in a mixture of water (5 ml) and ethanol 1 ml) was heated under reflux for 20 hours. The cool reaction solution was extracted with dichloromethane (5×30 ml), then the combined extracts dried (Na2SO4) and evaporated under vacuum to give the crude product. Purification by column chromatography (SiO2, 5% MeOH in CH2Cl2) afforded the title compound as a white solid (0.45 g, 89%). Crystallisation of a sample from ethyl acetate-hexane gave colourless needles, m.p. 154-155° C. Found: C,64.45; H,5.97; N,18.89. C16H18N4O2 requires C,64.41; H,6.08; N,18.78%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:23])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:23])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:21])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CNCCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101 %

Procedure:
A solution of (±)-tert-butyl 4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (93.7 g, 0.276 mol) in dioxane (100 mL) was treated with 4 M HCl solution in dioxane (275 mL, 1.1 mol). The resulting mixture was stirred at room temperature for four hours. After this time, the mixture was concentrated in vacuo, and then concentrated 3× from methylene chloride (200 mL) to remove residual HCl. The resulting residue was stirred in 1 M NaOH (500 mL), and the resulting suspension was extracted 4× with 500 mL of ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield the title compound (66.8 g, quantitative yield) as a solid.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([NH:18][C:19]([C:21]2[S:35][C:24]3=[N:25][CH:26]=[C:27](C4C=NC=CC=4)[N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[CH3:40][N:41]([CH3:57])[C:42]1[N:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][N:43]=1>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:36])=[C:16]([NH:18][C:19]([C:21]2[S:35][C:24]3=[N:25][CH:26]=[C:27]([C:45]4[CH:46]=[N:47][C:42]([N:41]([CH3:40])[CH3:57])=[N:43][CH:44]=4)[N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(-c3cccnc3)cnc2s1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(-c3cnc(N(C)C)nc3)cnc2s1
Yield: 13 %

Procedure:
Preparation analogous to the synthesis of 25h by using 2-dimethylamino-pyrimidine-5-boronic acid pinacol ester (1.5 eq). Purified by HPLC to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-(2-(dimethylamino)pyrimidin-5-yl)thieno[2,3-b]pyrazine-6-carboxamide 25k (4 mg, 13%).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[OH:5].[OH-].[Na+].Cl>CO>[C:9]1([CH3:12])[CH:8]=[CH:7][C:6]([C:4]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)([OH:5])[C:3]([OH:20])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C(O)(c1ccc(C)cc1)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(O)(C(=O)O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 22 (613 mg, 2.26 mmol) in methanol (75 mL) was treated with 1 N NaOH (10 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was neutralized with 1 N HCl and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and 1 N HCl solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (23). The crude product was used directly.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]I>CN(C=O)C>[CH3:18][N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]1=2
Reactant: CI
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
7-Nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (200 mg, 0.97 mmol) was dissolved in anhydrous DMF (3 ml), and treated with sodium hydride (60% in mineral oil, 58 mg, 1.45 mmol) followed by methyl iodide (0.5 ml). The mixture was stirred 18 hours at room temperature, and then partitioned between ethyl acetate (30 ml) and water (30 ml). Washing once with water (30 ml), drying over anhydrous magnesium sulfate and concentration gave a yellow residue. Purification by preparative TLC (40% EtOAc/hexane) gave 1-Methyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one as a white solid, 185 mg. (87% yield) 1H NMR (400 MHz, DMSO-d6) δ 8.14-8.24 (m, 2H), 7.52-7.60 (m, 1H), 3.40 (s, 3H), 2.75-2.82 (m, 2H), 2.06-2.25 (m, 4H); MS (m/e) 221 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:28](=[O:30])[CH3:29])=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])(C)(C)C.FC(F)(F)C(O)=O>O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH:17]([OH:18])[CH2:16][N:14]([CH3:15])[S:13]([C:12]2[CH:11]=[C:10]([C:28](=[O:30])[CH3:29])[S:9][C:8]=2[NH2:7])(=[O:27])=[O:26])=[CH:24][CH:23]=1
Reactant: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(N)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
(5-Acetyl-3-{[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-sulfamo yl}-thiophene-2-yl)carbamic acid t-butyl ester (1.3 g) was added to trifluoroacetic acid (10 mL). After stirred for 10 minutes at room temperature, water was added to the residue that was evaporated in vacuo, and the pH of saturated sodium bicarbonate was adjusted to 11. The solution was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride water, whereafter this solution was dried with anhydrous magnesium sulfate. The solid obtained by passing through a short column of NH-silica gel and evaporating the solvent at reduced pressure was washed with ethyl acetate, and the title compound (713 mg) was obtained as an ocher solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Mg].[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]>CCOCC>[NH2:14][C:13]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC#N
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C=C(N)c1ccc(C(F)(F)F)cc1
Yield: 87.4 %

Procedure:
To the Grignard reagent prepared from 98 g (0.436 mol) of p-bromobenzotrifluoride and 10.59 g (0.436 mol) of magnesium in ether was added 24.65 g (0.218 mol) of ethyl cyanoacetate dropwise with stirring and cooling in an ice bath. The resultant mixture was stirred at reflux for 24 hours. The usual workup gave 49.4 g of dark red-brown residue; distillation of this material gave 16.73 g (30%) of product, boiling point 120°-123° (0.15 torr).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[N:8]=1)=O.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(O)=O>[CH3:15][O:14][C:11]1[C:12](=[O:13])[C:7]([C:5]2[N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:2]=[CH:3][CH:4]=2)=[N:8][N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[CH:10]=1
Reactant: NNc1ccccc1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)C=CN(C)C)c1=O
Solvent: CC(=O)O
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (3.41 g, 9.29 mmol) and phenylhydrazine (1.83 mL, 18.6 mmol) in AcOH (25 mL) was refluxed for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed successively with 1 M HCl aqueous solution, 1 M NaOH aqueous solution, and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and crystallized from hexane/AcOEt to give the title compound (2.70 g, 71% yield) as colorless crystals: mp 139-141° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.98 (3H, s), 7.05 (1H, dd, J=1.9, 7.9 Hz), 7.19 (1H, s), 7.34-7.47 (7H, m), 7.56 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 7.92 (1H, s). LC-MS (ESI) m/z 413 [M+H]+. Anal. Calcd for C21H15F3N4O2: C, 61.17; H, 3.67; N, 13.59. Found: C, 61.15; H, 3.65; N, 13.57.
Reaction SMILES: F[C:2]([F:7])(F)[C:3](O)=O.[NH2:8][C:9]1[N:30]=[C:29](Cl)[CH:28]=[CH:27][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[S:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)=[O:12]>>[NH2:8][C:9]1[N:30]=[C:29]([NH:8][CH2:9][C:10]2[CH:27]=[CH:28][C:2]([F:7])=[CH:3][CH:11]=2)[CH:28]=[CH:27][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[S:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)=[O:12]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: O=C(O)C(F)(F)F
Product: Nc1nc(NCc2ccc(F)cc2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Yield: 16 %

Procedure:
The title compound (10.6 mg, 0.0188 mmol, 16%) was obtained as a trifluoroacetic acid salt from 2-amino-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (41 mg, 0.12 mmol) and 4-fluorobenzylamine (200 μl, 1.75 mmol) according to an analogous method to Example A-94.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH2:4].N1C=CC=CC=1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13].O>CN(C)C=O.C(OCC)(=O)C>[F:1][CH2:2][CH2:3][NH:4][C:12](=[O:13])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCF
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCCF)Oc1ccccc1
Yield: 86.5 %

Procedure:
After dissolving 2-fluoroethylamine (0.5 g, 5.0321 mmol) in dimethylformamide (10 ml), pyridine (0.87 ml, 10.5674 mmol) was added at room temperature and the mixture was stirred. It was then cooled on ice, phenyl chloroformate (0.67 ml, 5.2837 mmol) was added dropwise, and after the dropwise addition the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (0.797 g, 4.3509 mmol, 86.46%) as light yellow crystals.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:28])[NH:7][C:8]2[CH:27]=[CH:26][C:11]([O:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:27]=[CH:26][C:11]([O:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=2)=[O:28])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)NCC3CC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a stirring solution of tert-butyl 4-(4-(3-(cyclopropylmethyl)ureido)phenoxy)piperidine-1-carboxylate (2.57 mmol, 1 g) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for 30 minutes then was concentrated under vacuum. The residue was dissolved in dichloromethane and purified by SCX chromatography to give the title compound (350 mg). MS (ESI) m/z 290.1 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[S-:11][C:12]#[N:13].[K+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12](=[S:11])[NH2:13])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Product: NC(=S)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of 5-bromoindoline (14.8 g, 75 mmol) in 200 mL of 1N aqueous hydrochloric acid was treated with potassium thiocyanate (34.0 g, 350 mmol) in portions. The mixture was heated at reflux for 1 h and was then cooled to room temperature. The precipitate was collected, washed with water, and recrystallized from 2-propanol to afford (in two crops) 14.1 g (73%) of 5-bromoindoline-1-thiocarboxamide as a light yellow, fluffy solid.