Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:41])([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:29][N:28]=3)[CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[N:13]=1)(=O)C.C(=O)(O)[O-].[Na+]>O.CO>[CH3:41][C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:14]2[N:13]=[C:12]([CH2:11][OH:10])[O:16][N:15]=2)=[CH:18][CH:19]=1)([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:29][N:28]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(=O)OCc1nc(-c2ccc(C(C)(c3ccc(OCc4ccccn4)cn3)C(C)C)cc2)no1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)C(C)(c1ccc(-c2noc(CO)n2)cc1)c1ccc(OCc2ccccn2)cn1
Reaction time: 1 h

Procedure:
Potassium carbonate (743 mg, 5.38 mmol) in water (1.00 mL) was added to a stirred solution of 3c (0.896 mmol) in MeOH (3.00 mL) at rt. After approximately 1 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts were washed with water, brine, dried (sodium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-6% MeOH/DCM as eluent) to furnish the title compound 3d. m/z (ES) 431 (MH)+. 1HNMR. (500 MHz, CD3OD): δ 8.55 (d, 1H, J=3.3 Hz), 8.28 (d, 1H, J=2.7 Hz), 7.94 (d, 2H, J=8.5 Hz), 7.88 (dt, 1H, J=1.7, 7.7 Hz), 7.61 (d, 1H, J=7.8 Hz), 7.48 (d, 2H, J=8.5 Hz), 7.35 (m, 3H), 5.23 (s, 2H), 3.08 (m, 1H, J=6.6 Hz), 1.70 (s, 3H), 0.86 (d, 3H, J=6.6 Hz), 0.80 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Se].[OH2:14]>>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2]([CH:1]=[O:14])=[O:3])=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O
Agent: [Se]
Product: O=CC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
6.60 (40 mmol) 4-nitroacetophenone was dissolved in 30 ml of diozane and 5 g, (45 mmol) selenium dioxyde was dissolved in 2.2 ml water and mixed. The mixture was refluxed for 16 hours with continuous stirring. The reaction mixture was passed through an alumina column to remove selenium. The solvent was evaporated in vacuum. The crude product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.Cl.Cl.[CH2:20]([O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:27]([O:36][CH2:37][CH3:38])=[CH:26][C:24]=1[NH2:25])[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:27]([O:36][CH2:37][CH3:38])=[CH:26][C:24]=1[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)[CH3:21]
Reactant: CCOc1cc(N2CCOCC2)c(OCC)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Agent: Cl
Product: CCOc1cc(N2CCOCC2)c(OCC)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5-diethoxy-4-morpholinoaniline dihydrochloride (98 mg, 0.290 mmol) similar to Example 117 and isolated as a brown oil (3 mg, 3%). 1H NMR (CDCl3): 9.64–9.63 (m, 1H), 8.74–8.69 (m, 2H), 7.42–7.38 (m, 1H), 7.33 (s, 1H), 6.83 (s, 1H), 6.60 (s, 1H), 4.13 (q, J=7.2 Hz, 4H), 3.92–3.89 (m, 4H), 3.14–3.11 (m, 4H), 1.26 (t, J=7.2 Hz, 6H).
Reaction SMILES: [NH2:1][CH:2]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:3]1[N:12]=[C:11]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C[CH2:28][OH:29]>C(OCC)=O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH:2]([C:3]2[N:12]=[C:11]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)[NH:1][CH:28]=[O:29])=[CH:25][CH:24]=1
Reactant: Cc1cc(Nc2nc(C(N)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Reactant: CCO
Solvent: CCOC=O
Product: Cc1cc(Nc2nc(C(NC=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 120 °C
Yield: 8 %

Procedure:
To 2-(amino(4-fluorophenyl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine from Example 45 Step B (0.1 g, 0.28 mmol) in ethyl formate (4 mL) were added TEA (0.2 mL) and EtOH (0.5 mL), and the mixture was heated to 120° C. for 30 min in a Biotage microwave reactor and then concentrated under reduced pressure. The residue was diluted with DMSO (5 mL) and purified by reverse-phase preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/MeOH and solvent A=0.05% HOAc/H2O) to afford N-((4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methyl)formamide (8 mg, 8%). 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3H) 6.07 (d, 1H) 6.44 (s, 1H) 7.16 (t, 2H) 7.4-7.6 (m, 3H) 7.8 (m, 2H) 8.21 (s, 1H) 8.62 (d, 1H) 9.06 (d, 1H) 10.48 (bs, 1H) 12.17 (bs, 1H); LC-MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[C:19]([F:22])([F:21])[F:20])(C)(C)C.FC(F)(F)C(O)=O>ClCCCl>[CH3:6][NH:7][C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[C:19]([F:21])([F:20])[F:22]
Reactant: CN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1C(F)(F)F
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1sc(-c2cccnc2)nc1C(F)(F)F
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of DCE (4 mL) was added methyl-(2-pyridin-3-yl-4-trifluoromethyl-thiazol-5-yl)-carbamic acid tert-butyl ester (0.616 g, 1.7 mmol) and trifluoroacetic acid (4 mL) and the mixture was stirred for 15 min. The solvents were removed under reduced pressure and the resulting residue was re-dissolved in DCE and aqueous saturated NaHCO3. The biphasic mixture was separated and the aqueous layer was extracted three times with DCE. The organic extracts were combined, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as an off-white solid (0.357 g, 80%): mp 152-157° C.; 1H NMR (300 MHz, CDCl3) δ 8.95 (d, J=2.3 Hz, 1H), 8.57 (dd, J=4.9, 1.7 Hz, 1H), 8.11 (dt, J=8.2, 2.3 Hz, 1H), 7.23 (ddd, J=7.9, 4.9, 0.7 Hz, 1H), 4.83 (br s, 1H), 3.05 (d, J=4.9 Hz, 3H); ESIMS m/z 260 (M+1), m/z 257.9 (M−1).
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][N:19]1[C:24](=[O:25])[C:23]2[CH:26]=[CH:27][S:28][C:22]=2[N:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:20]1=[O:33]>ClCCCl>[CH3:18][N:19]1[C:24](=[O:25])[C:23]2[CH:26]=[C:27]([C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:12])[S:28][C:22]=2[N:21]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:20]1=[O:33]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(=O)c3cccc4ccccc34)sc21
Temperature: 25 °C

Procedure:
1-Naphthoyl chloride (1.25 ml) was added under nitrogen to a stirred slurry of aluminium chloride (1.1 g) in 1,2-dichloroethane (10 ml). A solution of 3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(2.0 g) in 1,2-dichloroethane (10 ml) was added dropwise and the resultant mixture was heated under reflux for 24 h and then allowed to cool to ambient temperature. The reaction mixture was quenched by the careful addition of water (2 ml) and was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed thrice with dilute hydrochloric acid, twice with saturated sodium hydrogen carbonate solution, and once with brine, then dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on silica gel eluting with toluene:ethyl acetate (9:1) gave the title compound (0.78 g).
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][CH:4]([NH2:18])[CH2:3][CH:2]([F:1])[CH2:8]1)=[O:48]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)CC(F)C1

Procedure:
Following the procedure for Example 101, Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (273 mg, 19% over three steps). Compound 154 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 7.61-7.41 (m, 4H), 7.27 (dd, J=14.5, 5.8 Hz, 2H), 4.84-4.56 (m, 1H), 3.67 (d, J=7.4 Hz, 3H), 3.44-3.34 (m, 2H), 3.21-2.86 (m, 3H), 2.22-2.07 (m, 1H), 1.87 (ddt, J=34.3, 21.1, 7.4 Hz, 3H), 1.70-1.53 (m, 1H). MS (ESI) m/z: 466.1 [M+H+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]#[N:11].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O.Cl>[O:7]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:9]1[C:10]#[N:11]
Reactant: O=C1CCOCC1
Reactant: N#CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: N#CC1OC12CCOCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of dihydro-2H-pyran-4(3H)-one (10.0 g) and 2-chloroacetonitrile (7.5 g) in tert-butanol (10 mL) was treated with 1.0 N potassium tert-butoxide (100 mL) drop-wise over 20 minutes. The reaction mixture was stirred at room temperature for 16 hours. It was diluted with water (10 mL) and 10% aqueous HCl (20 mL). The reaction mixture was concentrated to one-third of its original volume, and extracted with diethyl ether four times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel eluting with 20-40% ethyl acetate in hexanes.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:34])[N:19]([CH3:33])[N:20]([CH3:32])[C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24](S(C)(=O)=O)[N:23]=2)=[CH:13][CH:12]=1>C1COCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:34])[N:19]([CH3:33])[N:20]([CH3:32])[C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:23]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: Cn1c(-c2ccnc(S(C)(=O)=O)n2)c(-c2ccc(F)cc2)c(=O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccnc(Oc3ccccc3)n2)c(-c2ccc(F)cc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of phenol (0.12 g, 1.29 mmol) in THF (5 mL) is added sodium hydride (0.04 g, 1.08 mmol). After stirring at room temperature for 10 min, a solution of 4-(4-fluorophenyl)-1,2-dimethyl-5-(2-methanesulfonyl-pyrimidin-4-yl)-1,2-dihydropyrazol-3-one, 30, (0.20 g, 0.55 mmol) in THF (5 mL) is added to the reaction mixture. The mixture is stirred at room temperature for 4 hours. The reaction is then quenched with H2O and diluted with EtOAc. The organic phase is washed with 1N NaOH (×2), dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified by preparatory HPLC to the desired product: 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J=4.8 Hz, 1H), 7.48 (t, J=8.1 Hz, 2H), 7.36-7.31 (m, 3H), 7.24 (dd, J=7.5, 1.2 Hz, 2H), 7.04 (t, J=9.0 Hz, 2H), 6.94 (d, J=5.1 Hz, 1H), 3.53 (s, 3H), 3.38 (s, 3H); HRMS calcd for C21H18FN4O2 (M+H)+377.1418; found 377.1397.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32]C)=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:36])[CH2:8][C:9]([CH3:35])([CH3:34])[O:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].CO>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([OH:32])=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:19][CH2:20]2)=[C:11]2[C:6]([C:7](=[O:36])[CH2:8][C:9]([CH3:34])([CH3:35])[O:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(=O)O)cc43)CC1)OC(C)(C)CC2=O
Temperature: 40 °C
Reaction time: 20.5 h

Procedure:
4.0 g of the above crude product of methyl 1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxylate was dissolved in 40.0 mL of tetrahydrofuran and added with 16 mL of 1 N aqueous sodium hydroxide. 20 mL of methanol was added to remove the separation of layers of the reaction mixture, and the reaction mixture was stirred at 40° C. for about 20.5 hours. When the reaction mixture was cooled with an ice-water bath and the pH was adjusted to 7 with 15 mL of 1 N hydrochloric acid, crystals precipitated. 10 mL of water was further added to this slurry, and crystals were obtained by filtration and the crystals were washed with 24 mL of a mixture of 2-propanol and water (1:5). The crystals were dried in vacuo and 3.34 g of the title compound was obtained.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[C:16]1([Mg]Br)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.O.Cl>CC1C=CC=CC=1C.O1CCCC1>[OH:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[P:2]([C:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1)[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Reactant: Br[Mg]c1cccc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1C
Product: Oc1ccccc1-c1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Temperature: 25 °C
Yield: 69.7 %

Procedure:
14.1 g (60 mmol) of 6-chloro-6H-dibenz[c,e][1,2]-oxaphosphorine in 50 ml of anhydrous o-xylene are introduced, in an argon atmosphere with stirring, and a solution of 150 mmol of 1-naphthylmagnesium bromide in tetrahydrofuran is added dropwise. The temperature increases in the course of this from 25° to 45° C. The mixture is then stirred for 3 hours at 80° C. and 5 hours at 120° C. The mixture is cooled to room temperature and 100 ml of water are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 19.0 g of colorless oil are obtained. By crystallization with methanol/water, 10:1, 22.8 g (89%) of colorless crystals having melting point 255° to 256° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S-:9][C:10]#[N:11].[NH4+].BrBr.N.Br>C(O)(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([S:9][C:10]#[N:11])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccccc1F
Reactant: N#C[S-]
Agent: Br
Agent: BrBr
Agent: N
Solvent: CC(=O)O
Product: N#CSc1ccc(N)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 22.2 g of 2-fluoroaniline in 100 mL of acetic acid is added 32 g of ammonium thiocyanate. The flask is immersed in an ice bath and the mixture stirred during the dropwise addition of 32 g of bromine in 40 mL of acetic acid. After the addition, which takes ca 40 min., the mixture is stirred for 1 h at 0° C. and them dumped into 700 mL of rapidly stirred icewater. Conc. aqueous ammonia is added to neutralize HBr and bring the pH of the mixture to 4.0. The resulting yellow solid is filtered, washed well with water, and dried in vacuo to provide 27.72 g of 4-amino-3-fluorobenzenesulfenyl cyanide as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[C:7]1([NH2:17])[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.ClCCNC(N)=O.CO>O1CCCC1.O>[C:7]1([NH:17][C:5]2[O:6][CH2:2][CH2:3][N:4]=2)[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: O=C=NCCCl
Agent: NC(=O)NCCCl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: c1cc2c(c(NC3=NCCO3)c1)CCCC2
Temperature: 25 °C

Procedure:
Chloroethylisocyanate (Compound 5 210 mg, 2.05 mmol) was added to a stirred solution at 5,6,7,8-tetrahydro-1-naphthylamine (302 mg, 2.05 mmol) in tetrahydrofuran (2 ml). After 30 minutes the resulting chloroethylurea was collected by vacuum filtration. Yield: 302 mg (58%) of fine white crystals: mp 101°-103°; 1H NMR (300 MHz, CDCl3) & 6.98-7.30 (m, 3H); 6.08 (br s, 1H); 5.19 (br s, 1H); 3.68 (m, 2H); 3.55 (m, 2H); 2.79 (m, 2H); 2.61 (m, 2H); 1.80 (m, 4H); Mass spectrum m/e 252.1034 (C13H17ClN2O requires 252.1029). The chloroethyl urea (237 mg, 0.94 mmol) was suspended in H2O (3 ml) and CH3OH (3 ml) and heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and worked up as above to yield after recrystallization (hexane/CHCl3) 187.6 mg (87%) of the title compound: mp 160°-162° C.; 1H NMR (300 MHz, CDCl3) & 7.23 (m, 1H); 7.08 (m, 1H; 6.75 (m, 1H); 5.55 (br, 1H); 4.35 (t, 2H); 3.70 (t, 2H); 2.70 (m, 2H); 2.58 (m, 2H); 1.80 (m, 4H); Mass spectrum m/e 216.1257 (C13H16N2O requires 216.1262).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][C:22]=1[CH3:30])=[C:19]=[S:20]>O1CCCC1>[C:25]([C:24]1[CH:28]=[CH:29][C:21]([NH:18][C:19]([NH:1][C:2]2[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=2[Cl:12])[C:5]([O:7][CH3:8])=[O:6])=[S:20])=[C:22]([CH3:30])[CH:23]=1)(=[O:26])[NH2:27]
Reactant: Cc1cc(C(N)=O)ccc1N=C=S
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(C(N)=O)cc2C)c1NCCCO
Temperature: 60 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (2.09 g, 8.08 mmol) and 4-isothiocyanato-3-methylbenzamide (2.33 g, 12.1 mmol) in tetrahydrofuran (20 mL) was stirred at 60° C. for 2 days. The mixture was concentrated in vacuo, and the residue was washed with ethyl acetate to give methyl 3-{[(4-carbamoyl-2-methylphenyl)carbamothioyl]amino}-4-chloro-2-[(3-hydroxypropyl)amino]benzoate as a colorless powder (2.10 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1.[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH:9]=1
Reactant: N#Cc1cccc(-c2ccccc2Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1cccc(-c2nnn[nH]2)c1
Temperature: 90 °C

Procedure:
A mixture of 2′-bromo-biphenyl-3-carbonitrile (200 mg, 0.77 mmol), sodium azide (66 mg, 1.01 mmol) and triethylamine hydrochloride (139 mg, 1.01 mmol) in toluene (2 ml) was heated at 90° C. for 24 hours. A further portion of sodium azide (66 mg, 1.01 mmol) and triethylamine hydrochloride (139 mg, 1.01 mmol) was added and heated for a further 24 hours. After cooling, the mixture was extracted with water (3×2 ml). The combined extracts were acidified and the precipitate filtered off and dried. (163 mg, 70%).
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:16])=[CH:12][N:11](C4CCCCO4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[C:30]([N:31]2[CH2:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:16])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCCOCC3)cc2[nH]1)N1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1c[nH]nc1-c1nc2cc(F)c(N3CCCOCC3)cc2[nH]1)N1CCCCC1
Temperature: 22 °C
Yield: 97.2 %

Procedure:
A solution of 80 mg of N-[3-(5-fluoro-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]piperidine-1-carboxamide in solution in 4 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. for 1 hour. The reaction medium is concentrated under vacuum in a rotary evaporator, and then reacted again at 22° C. for 16 hours with 4 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. The reaction medium is concentrated under vacuum in a rotary evaporator. The product is made into a paste in isopropyl ether, but the product is hydroscopic. The reaction crude is purified by flash chromatography, elution being carried out with a mixture of cyclohexane/ethyl acetate then dichloromethane/methanol. The product is diluted in ethyl acetate, and washed with 2 times 5 mL of a 2N aqueous solution of sodium hydroxide. The aqueous phases are extracted with 3 times 10 mL of ethyl acetate. The organic phases are dried over MgSO4, filtered and concentrated under vacuum in a rotary evaporator. 65 mg of N-[3-(5-fluoro-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]piperidine-1-carboxamide are obtained in the form of a gray solid.
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33].C[CH2:35][N:36]=[C:37]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N(C)C.Cl>C(Cl)Cl>[CH3:35][N:36]([CH3:37])[C:30]([C:26]1[CH:25]=[C:24]2[C:4]3([CH2:5][CH2:6][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])[CH2:8][CH2:9]3)[C:3](=[O:33])[N:2]([CH3:1])[C:29]2=[CH:28][CH:27]=1)=[O:31]
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc2c(c1)C1(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a mixture of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (20 mg, 0.508 mmol), EDCI (18 mg, 0.088 mmol), HOBt (12 mg, 0.088 mmol), and DIEA (60 mg, 0.44 mmol) in CH2Cl2 was added NHMe2.HCl (16 mg, 0.176 mmol) at 0° C. The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by preparative TLC to give (E)-N,N,1-trimethyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide (6 mg, 14%). 1H NMR (400 MHz, CDCl3): δ=3.05 (m, 6H), 3.25 (m, 3H), 3.60-3.75 (m, 2H), 3.95 (m, 2H), 4.15 (m, 1H), 4.35 (m, 1H), 6.85 (m, 1H), 7.35 (m, 1H), 7.45 (m, 2H), 7.55 (m, 1H) 7.70 (m, 2H), 8.00 (m, 1H).