Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[K+]>O>[I:22][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: [I-]
Reactant: CCOC(=O)c1c(C)n[nH]c1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c(C)n[nH]c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
Ethyl 5-amino-3-methyl-1H-pyrazole-4-carboxylate (2.1 g, 12.41 mmol, 1.00 equiv) was added in portions to a solution of sulfuric acid (98%, 6 mL) in 5 mL water at 0° C. The resulting solution was stirred at 0° C. for 30 min. A solution of sodium nitrite (1.28 g, 18.55 mmol, 1.49 equiv) in 5 mL water was added dropwise to the reaction mixture at 0° C. The resulting solution was stirred at 0° C. for another hour. A solution of potassium iodide (4.2 g) in 5 mL water was then added dropwise. The resulting solution was stirred at 25° C. for 8 h. The reaction mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers was washed sequentially with 1×100 mL of saturated Na2SO3 solution and 2×100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-30% of ethyl acetate in petroleum ether to give 2.1 g (60%) of ethyl 5-iodo-3-methyl-1H-pyrazole-4-carboxylate as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ4.32 (q, J=7.2 Hz, 2H), 2.61 (s, 3H), 1.38 (t, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.24 min, m/z=281.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.[C:28]1(=O)[CH2:31][CH2:30][CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH:28]1([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:10]3[C:5]([O:4][C:3]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=4[Cl:1])=[N:6][CH:7]=[CH:8][CH:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (50 mg, 0.125 mmol, 1.0 equiv; Example 122) in cyclobutanone (469 mg, 0.5 mL, 6.69 mmol, 53.5 equiv; [CAS RN 1191-95-3]) was added acetic acid (28 mg, 27 μL, 0.5 mmol, 4.0 equiv; [CAS RN 64-19-7]) and the reaction mixture stirred at rt. After 90 min, sodium cyanoborohydride (15.7 mg, 0.25 mmol, 2.0 equiv; [CAS RN 25895-60-7]) was added and stirring at rt continued for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 12.5 mg (22%) of the title compound. MS (ISP): 454.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[CH:15]=[CH:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38](O)=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:21][C:38]([C:33]1[C:32]([C:29]3[CH:28]=[CH:27][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:31][CH:30]=3)=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:39])[CH:15]=[CH:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(-c2ccccc2C(=O)O)cc1
Reactant: Nc1ccc2cc(C(=O)OCc3ccccc3)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2ccccc2C(=O)Nc2ccc3cc(C(=O)OCc4ccccc4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.4 %

Procedure:
To solution of 2-aminoquinoline-6-carboxylic acid benzyl ester (25 g, 100 mmol) and 4′-tert-butylbiphenyl-2-carboxylic acid (19.5 g, 70 mmol) in CH2Cl2 (500 mL) was added 4-dimethylaminopyridine (9.77 g, 80 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.2 g, 100 mmol). The reaction mixture was stirred at room temperature for 18 h and then diluted with saturated aqueous NaHCO3 solution. The aqueous phase was separated and extracted with CH2Cl2. Combined organic layers were washed with brine, dried over MgSO4 and concentrated. The title compound (28.6 g, 79%) was isolated by column chromatography eluting with a gradient of 5% to 30% EtOAc in hexane.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:22][CH2:21]1
Reactant: OC1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(O)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (166.6 mg, 0.55 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 4-Hydroxypiperidine (Fluka)(55.8 mg; 0.55 mmol; 1 eq.) and triethylamine (0.15 ml; 1.10 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (29) as a brown solid (80.3 mg; 40%). 1H NMR (DMSO-d6, 300 MHz) δ 1.44 (m, 2H), 1.82 (m, 2H), 2.14 (s, 3H), 2.50 (s, 3H), 3.35 (m, 2H), 3.80 (m, 2H), 4 (m, 1H), 4.60 (m, 1H), 7.98 (s, 1H), 12.16 (br s, 1H). M− (ESI): 365; M+ (ESI): 367. HPLC (method A), Rt: 2.31 min (purity: 91.1%).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]([C:27]1[N:31](COCC[Si](C)(C)C)[C:30]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=2[N:28]=1)(O)[C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].FC(F)(F)C(C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1)(O)C1C(SC)=CC(C)=C2C=1C=C[N:55]2S(C1C=CC(C)=CC=1)(=O)=O.Cl.S(Cl)(Cl)=O.C(O)C>CN(C=O)C.N>[NH2:55][C:3]([C:27]1[NH:31][C:30]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=2[N:28]=1)([C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:17])=[O:18])[C:2]([F:47])([F:46])[F:1]
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl
Agent: N
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(N)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a mixture of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 14-A) (425 mg, 0.6 mmol) was added HCl (1.25M in MeOH, 4.85 mL, 6.06 mmol) and the mixture was stirred at 60° C. After 40 minutes the mixture was cooled to room temperature and concentrated. The mixture was dissolved in CHCl3 (12 mL), then was added thionyl chloride (0.44 mL, 6.06 mmol) and one drop of DMF and the mixture was heated at 70° C. After 4 hours the reaction was cooled to room temperature and stirred at room temperature overnight. The reaction was then concentrated, dissolved in ammonia in ethanol (2.0M, 30.3 mL, 60.6 mmol) and stirred at room temperature. After 15 minutes the reaction was concentrated and purified directly by flash chromatography (0-70% EtOAc in heptanes). MS (ESI+) m/z 570.3 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[C:7]([S:13]([N:16]=[CH:17][N:18]([CH3:20])[CH3:19])(=[O:15])=[O:14])[CH:6]=1)([CH3:4])[CH3:3].B(Br)(Br)Br>C(Cl)Cl>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:13]([N:16]=[CH:17][N:18]([CH3:20])[CH3:19])(=[O:14])=[O:15])[CH:6]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)(=O)N=CN(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)ccc1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2.98 g (0.01 mol) of 4-(1,1-dimethylethyl)-2-dimethylaminomethyleneaminosulfonylanisole are dissolved in 30 ml of methylene chloride, and 2.75 g (0.011 mol) of boron tribromide are added. The mixture is stirred at room temperature for 45 minutes and then excess boron tribromide is destroyed by cautiously adding methanol. The mixture of solvents is removed in vacuo and the residue is triturated with water. The product results in the form of pale yellowish crystals. Isopropanol is used for recrystallization.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:27])=[C:8]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:27])=[C:8]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(C(F)(F)F)cc21
Yield: 30.5 %

Procedure:
1,1-Dimethylethyl N-((7-trifluoromethyl-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (380 mg, 919 μmol) was stirred in TFA (2 mL, 26924 μmol) at room temperature for 30 minutes. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried (MgSO4), and concentrated in vacuo to give a yellow solid. The solid was then washed with water, ether, and EtOAc to give the desired product as an off-white solid (100 mg). MS (m/e)=358.1 (M+H)+. Calculated for C16H14F3NO5 357.08.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([NH2:18])=[CH:20][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ccc(N)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(N)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 4-aminobenzylamine in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([Br:19])=[CH:12][CH:13]=2)[CH:8]=1)=[O:6]>O.C(O)C>[Br:19][C:11]1[CH:10]=[C:9]2[C:14]([CH:15]=[C:16]([O:17][CH3:18])[C:7]([C:5]([OH:6])=[O:4])=[CH:8]2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc2cc(Br)ccc2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2ccc(Br)cc2cc1C(=O)O
Yield: 94.8 %

Procedure:
A solution of sodium hydroxide (1.6 g, 40 mmol) in water (30 mL) was added to a solution of 7-bromo-3-methoxy-naphthalene-2-carboxylic acid methyl ester (5.9 g, 20 mmol) in ethanol (100 mL) and the resulting mixture was heated at reflux for 2 hours. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was acidified until pH 3 ca. by addition of an aqueous solution of hydrochloric acid. The resulting mixture was extracted twice with dichloromethane and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 5.329 g of 7-bromo-3-methoxy-naphthalene-2-carboxylic acid as a cream colored solid.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:24]=[CH:23][C:22]([NH:25][C@@H:26]4[CH:33]5[CH2:34][N:29]6[CH2:30][CH:31]([CH2:35][CH:27]4[CH2:28]6)[CH2:32]5)=[CH:21][CH:20]=3)=[CH:11]2)(=O)=O)C=CC=CC1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[N:24]=[CH:23][C:22]([NH:25][C@@H:26]3[CH:33]4[CH2:34][N:29]5[CH2:30][CH:31]([CH2:35][CH:27]3[CH2:28]5)[CH2:32]4)=[CH:21][CH:20]=2)=[CH:11]1
Reactant: O=S(=O)(C1C=CC=CC1)n1cc(-c2ccc(NC3C4CC5CC3CN(C5)C4)cn2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc2c(-c3ccc(NC4C5CC6CC4CN(C6)C5)cn3)c[nH]c2c1

Procedure:
A solution of the product of Example 162A (50 mg, 0.103 mmol) and potassium carbonate (34 mg, 0.25 mmol) in methanol (3 mL) was heated to reflux for 90 minutes. After cooling, the solvent was removed, the residue was dissolved in water, and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated to afford the free base of the title compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.68 (s, 1H), 1.86 (d, J=14.9 Hz, 2H), 1.96 (s, 2H), 2.29 (d, J=12.2 Hz, 2H), 3.09-3.29 (m, 8H), 3.81 (s, 1H), 7.01-7.24 (m, 3H), 7.40 (d, J=7.1 Hz, 1H), 7.50-7.61 (m, 2H), 7.98 (d, J=7.5 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H). MS (DCI/NH3) m/z=345 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:30][C:31]#[N:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.[NH2:37][OH:38]>CS(C)=O>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:30][C:31](=[N:37][OH:38])[NH2:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC#N)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Solvent: CS(C)=O
Product: CC(C)(C)C(CC(N)=NO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 140 °C

Procedure:
To a solution of racemic 3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-4,4-dimethyl-pentanenitrile, 124a, (0.059 g, 0.116 mmol) in DMSO (0.500 mL) was added hydroxylamine (0.031 g, 0.470 mmol). The mixture was heated in a microwave at 140° C. for 30 minutes. The residue was purified on a C18 column (acetonitrile/0.1% formic acid) to afford the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.58 minutes (M+H) 390.06.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][N:8]([CH2:10][CH2:11][CH:12]1[CH2:18][N:17](CC2C=CC=CC=2)[C:16](=[O:26])[C:15]2[CH:27]=[CH:28][CH:29]=[N:30][C:14]=2[O:13]1)[CH3:9].[OH-].[Na+].CN(C)C=O>O>[CH3:9][N:8]([CH3:7])[CH2:10][CH2:11][CH:12]1[CH2:18][NH:17][C:16](=[O:26])[C:15]2[CH:27]=[CH:28][CH:29]=[N:30][C:14]=2[O:13]1
Reactant: CN(C)CCC1CN(Cc2ccccc2)C(=O)c2cccnc2O1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCC1CNC(=O)c2cccnc2O1
Reaction time: 0.33 h

Procedure:
A solution of 3.0 g (0.006 mole) of 2-[2-(dimethylamino ethyl]-2,3-dihydro-4-phenylmethylpyrido[3,2-f][1,4]oxazepin-5(4H)-one oxalate[1:1.5]-hemihydrate in about 50 ml of water was made basic with dilute aqueous sodium hydroxide solution and then extracted with three 50 ml portions of benzene. The combined benzene extract was dried over anhydrous sodium sulfate and concentrated on the rotary evaporator (steam bath/50 mm). The residue was dried further by azeotroping 2 times with about 50 ml of dry benzene, evaporating to dryness each time. The final residue was dissolved in 40 ml of liquid ammonia and small spheres of sodium were added with stirring to the solution until a blue color persisted for 20 minutes. (Addition time was about 1 hr). Three grams of ammonium chloride was added slowly and the ammonia was allowed to evaporate. The residue was suspended in chloroform and the mixture was filtered. The filtrate was concentrated and the residue chromatographed on preparative high pressure liquid chromatograph using a silica gel column and eluting with 75% ethyl acetate/25% dimethylformamide. The yield of product was 0.1 g (7%). The chemical ionization mass spectrophotometer gave a peak at 236 corresponding to a molecular weight of 235. The 1H NMR spectrum of the subject compound was obtained in CDCl3 containing 1% tetramethylsilane (TMS) and is consistent with the proposed structure and dimethylformamide (DMF) and mineral oil as minor impurities. The chemical shifts, multiplicities, and assignments are given below:
Reaction SMILES: [CH2:1]([Si:4]([CH2:12][CH:13]=[CH2:14])([CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:6][CH2:7]Br)[CH:2]=[CH2:3].[CH2-]C(C)=O.[OH:19][CH2:20][CH:21]([CH2:23]O)[OH:22].[SiH4]>O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([Si:4]([CH2:12][CH:13]=[CH2:14])([CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:6][CH2:7][CH2:23][CH:21]([CH2:20][OH:19])[OH:22])[CH:2]=[CH2:3]
Reactant: C=CC[Si](CC=C)(CC=C)CCCBr
Reactant: OCC(O)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [CH2-]C(C)=O
Solvent: C1CCOC1
Product: C=CC[Si](CC=C)(CC=C)CCCCC(O)CO

Procedure:
Triallyl glycerylpropyl silane was prepared from triallyl bromopropyl silane prepared in Example 7 via glycerol acetonide intermediate. A 250 ml flask equipped with a stir bar was charged with 22.9 grams of 74% triallyl bromopropyl silane reagent (17.0 grams, 62 millimoles of triallyl bromopropyl silane prepared as described in Example 7). The silane was diluted with 175 ml of tetrahydrofuran (commercially available from Aldrich Chemical Co. of Milwaukee, Wis.) containing 1.1 grams (3.2 millimoles) tetrabutylammonium hydrogen sulfate (commercially available from Aldrich Chemical Co.). The reaction vessel was then cooled in an ice bath and purged with nitrogen.
Reaction SMILES: Cl[C:2]([CH:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5].[OH-].[NH4+:12].O>C(O)C>[NH2:12][C:2]([CH:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: CC(C)C(Cl)=C(C#N)C#N
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(N)=C(C#N)C#N
Temperature: 0 °C
Reaction time: 3.75 h

Procedure:
A solution of 530.5 g of 3-chloro-2-cyano-4-methyl-2-pentenenitrile in 515 ml of ethanol was added dropwise during one hour to a stirred solution of 2,400 ml of concentrated ammonium hydroxide in 1,560 ml of ethanol while maintaining the reaction mixture at 35°-40° with an ice-water bath. The reaction mixture was stirred for 3.5-4 hours and was poured into 6.5 liters of ice and water. The mixture was stirred until all the ice had melted (approximately thirty minutes). The precipitate was collected by filtration. The filter cake was washed with two 1500-ml portions of water and air-dried on the filter. After the drying the 400 g of 3-amino-2-cyano-4-methyl-2-pentenenitrile, mp 182°-184°, was used in the next synthesis step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])([C:12]2[CH:17]=[C:16]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:15]=[C:14]([F:25])[CH:13]=2)[CH2:9][CH:10]=[CH2:11])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].[CH2:39]([Zn]CC)C.ICI.Cl>C1(C)C=CC=CC=1>[CH:10]1([CH2:9][C@@:8]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:35]([F:38])([F:36])[F:37])[CH:4]=2)[C:12]2[CH:17]=[C:16]([O:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[CH:15]=[C:14]([F:25])[CH:13]=2)[CH2:39][CH2:11]1
Reactant: C=CC[C@](NC(=O)NCC(F)(F)F)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: ICI
Solvent: Cc1ccccc1
Product: O=C(NCC(F)(F)F)N[C@@](CC1CC1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 31.9 %

Procedure:
At 0° C. under argon, to a solution of (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)but-3-enyl)-3-(2,2,2-trifluoroethyl)urea (40 mg, 0.070 mmol), prepared as described in Procedure 6 and 10, in dry toluene (1 mL) was added diethyl Zinc (1.0 M in hexane, 1.2 mL, 1.2 mmol), followed by dropwise addition of diiodomethane (0.2 mL). The reaction mixture was gradually warmed to 110° C., and heated at 110° C. for 1 h. After cooling, 1 N HCl was added and the reaction mixture was stirred at room temperature for 5 min. The reaction mixture was extracted with EtOAc and the organic layer was washed with H2O, sat. NaHCO3, sat. NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5 u column eluting with 50-100% MeOH in H2O with 0.1% TFA, 40 mL/min, monitoring at 220 nm) to give (R)-1-(2-cyclopropyl-1-(4-fluoro-3-(trifluoromethyl)-phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea (Example 317) as white solid (13 mg, yield 32%). LCMS: RT=3.26 min [M+H] 583.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 50-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.55 (d, J=6.6 Hz, 1H), 7.46 (m, 1H), 7.12 (t, J=9.3 Hz, 1H), 6.94-6.85 (m, 3H), 5.84 (tt, J=52.8, 2.8 Hz, 1H), 5.61 (br, s, 1H), 4.78 (br, t, J=6.1 Hz, 1H), 3.69 (m, 2H), 2.31 (m, 2H), 0.36 (m, 3H), 0.00 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([C:31]#[N:32])=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([CH3:16])([CH3:15])[C:10]3[CH:17]=[C:18]([O:21][CH2:22][C@H:23]4[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]4)[CH:19]=[CH:20][C:9]=3[C:8](=[O:30])[C:7]2=1.[Cu][C:34]#[N:35].O>CC(N(C)C)=O>[CH3:29][C:25]1([CH3:28])[O:24][C@@H:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[C:2]([C:34]#[N:35])[C:3]([C:31]#[N:32])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:15])([CH3:16])[C:10]=3[CH:17]=2)[CH2:27][O:26]1
Reactant: N#C[Cu]
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4c(Br)c(C#N)ccc4c2C3=O)O1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4c(C#N)c(C#N)ccc4c2C3=O)O1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, 4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound U6, 20.0 mg, 40.37 μmol) was dissolved in DMA (0.35 mL), added with copper (I) cyanide (18.1 mg, 201.9 μmol), and stirred at 200° C. for 1 hr under irradiation with microwave. The reaction solution was poured into water, extracted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and then filtered. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound as a crude product.