Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C@@H:11]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[CH2:14][N:13](CC2C=CC(OC)=CC=2OC)[C:12]1=[O:37])[CH:9]=[CH2:10].C([C@H]1CC[C@H](C2C=CC=C(F)C=2F)CN(CC2C=CC(OC)=CC=2OC)C1=O)C=C>ClCCl>[CH2:8]([CH:11]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[CH2:14][NH:13][C:12]1=[O:37])[CH:9]=[CH2:10]
Reactant: C=CC[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2ccc(OC)cc2OC)C1=O
Agent: C=CC[C@H]1CC[C@H](c2cccc(F)c2F)CN(Cc2ccc(OC)cc2OC)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC1CCC(c2cccc(F)c2F)CNC1=O
Reaction time: 2.5 h

Procedure:
Trifluoroacetic acid (35 mL) was added to a solution of (3S,6S)-3-allyl-6-(2,3-difluorophenyl)-1-(2,4-dimethoxybenzyl)azepan-2-one and (3R,6R)-3-allyl-6-(2,3-difluorophenyl)-1-(2,4-dimethoxybenzyl)azepan-2-one (3.39 g, 8.15 mol) in dichloromethane (25 mL). After 2.5 h, the reaction mixture was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×). The organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. Purification by silica gel chromatography (98.5% dichloromethane/methanol→97% dichloromethane/methanol) gave the mixture of racemic trans compounds (3S,6S)-3-allyl-6-(2,3-difluorophenyl)azepan-2-one and (3R,6R)-3-allyl-6-(2,3-difluorophenyl)azepan-2-one and racemic cis compounds (3S,6R)-3-allyl-6-(2,3-difluorophenyl)azepan-2-one and (3R,6S)-3-allyl-6-(2,3-difluorophenyl)azepan-2-one. MS 266.1 (M+1).
Reaction SMILES: [CH:1]([Si:4]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:17]3[CH:18]=[C:19]([O:22][C@H:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C@@H:26]([NH2:33])[CH2:25][CH2:24]4)[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([O:61][Si:62]([CH:69]([CH3:71])[CH3:70])([CH:66]([CH3:68])[CH3:67])[CH:63]([CH3:65])[CH3:64])=[C:57]([Cl:72])[CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:33][C@@H:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]([O:22][C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([N:10]5[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:39])[CH3:38])[CH2:8][CH2:9]5)=[N:14][N:15]=4)[CH:18]=3)[CH2:24][CH2:25]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([O:61][Si:62]([CH:66]([CH3:68])[CH3:67])([CH:69]([CH3:70])[CH3:71])[CH:63]([CH3:65])[CH3:64])=[C:57]([Cl:72])[CH:56]=2)[N:48]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1Cl)(C(C)C)C(C)C
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5-c5ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(Cl)c5)c5ccccc54)cn23)CC1)(C(C)C)C(C)C

Procedure:
A solution of Intermediate G (153 mg, 0.28 mmol) and [5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporated herein by reference, 167 mg, 0.28 mmol) in 1,4-dioxane (4 mL) and DIPEA (87 μL, 0.50 mmol) was stirred at 95° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-7.5% MeOH in DCM, to give 1-[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(4-triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea (193 mg). This was dissolved in THF (3 mL) and treated with TBAF (1M in THF, 0.47 mL, 0.47 mmol). The solution was stirred at RT for 1.75 h, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-25% [2M NH3 in MeOH] in DCM, to give the product. This was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound (72 mg, 56%). LCMS (Method 5): Rt 3.99 min, m/z 685 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.38-1.52 (2H, m), 1.55-1.66 (1H, m), 1.73-1.96 (4H, m), 1.98-2.17 (2H, m), 2.85-2.97 (2H, m), 3.3-3.5 (4H, m, under water signal), 4.52 (1H, br s), 4.77-4.85 (1H, m), 5.55 (1H, br t, J=4.4 Hz), 6.28 (1H, s), 7.05 (1H, s), 7.08 (1H, s), 7.15 (1H, dd, J=2.0, 9.8 Hz), 7.23-7.40 (5H, m), 7.44 (1H, d, J=2.5 Hz), 7.61 (1H, d, J=9.9 Hz), 7.64 (1H, br d, J=1.5 Hz), 8.02 (1H, br s), 10.55 (1H, br s).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:36][CH2:37][C@H:38]([OH:48])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>>[OH:48][C@H:38]([CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1)[CH2:37][NH:36][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)(=[O:16])=[O:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(S(=O)(=O)c4ccc(C(F)(F)F)cn4)s3)cc2)CC1
Product: O=S(=O)(Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1)c1ccc(S(=O)(=O)c2ccc(C(F)(F)F)cn2)s1

Procedure:
The title compound was prepared from 5-(5-trifluoromethyl-pyridine-2-sulfonyl)-thiophene-2-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 229) and 4-((2S)-3-amino-2-hydroxy-propoxyl)-phenol (which was obtained in Example 5) according to the procedure of Example 278 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.25-1.45 (m, 2H), 1.70-1.95 (m, 2H), 2.50-2.85 (m, 5H), 3.54 (brd, J=12.4 Hz, 2H), 3.65-3.95 (m, 3H), 6.60-6.90 (m, 8H), 7.92 (d, J=1.6 Hz, 1H), 8.41 (d, J=8.3 Hz, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.61 (dd, J=8.3, 2.0 Hz, 1H), 8.89 (s, 1H), 9.23 (s, 1H); MS (ES) m/z: 713.1 (MH+); HRMS Calcd. for C30H32F3N4O7 S3 (MH+): 713.1385. Found: 713.1407.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CS(C)=O.[C-:39]#[N:40].[K+]>O>[C:39]([C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)#[N:40]
Reactant: O=C(c1c(F)ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F)c1c[nH]c2ncnc(Cl)c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Temperature: 150 °C
Yield: 13.1 %

Procedure:
To N-[3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1016, 62 mg, 0.12 mmol), 1.00 mL of dimethyl sulfoxide is added, followed by potassium cyanide (39.0 mg, 0.60 mmol). The reaction is heated at 150° C. in an oil bath for 4 hours, then at 150° C. overnight. The reaction is poured into water and extracted with ethyl acetate. The organic layer is concentrated under vacuum and purified by silica gel column chromatography, eluting with a gradient of 10-60% ethyl acetate in hexanes. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1023, 8 mg). MS (ESI) [M+H+]+=508.1.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:7]#[C:8][CH:9]=[O:10])[CH3:6])(=[O:3])[CH3:2].CC(=CC)C.[O-:16]Cl=O.[Na+]>CC(O)(C)C.O>[C:1]([O:4][C@@H:5]([CH3:6])[C:7]#[C:8][C:9]([OH:16])=[O:10])(=[O:3])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CC(=O)O[C@@H](C)C#CC=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)O[C@@H](C)C#CC(=O)O
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
To a solution of 9 (133 mg, 0.949 mmol) and 2-methyl-2-butene (1.20 mL, 14.2 mmol) in tBuOH (1.9 mL) was added the mixture of NaClO2 (257 mg, 2.84 mmol) and NaH2PO4 (393 mg, 2.84 mmol) in H2O (1.9 mL) at 23° C. The resulting mixture was stirred for 20 min at the same temperature and quenched by 1 N aqueous HCl (3 mL) at 0° C. The mixture was poured into a separatory funnel and diluted with EtOAc (3 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×4 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (silica gel 15 mL; 50→100% EtOAc in hexanes containing 1.0% acetic acid) afforded acid 10 (149 mg, quantitative yield) as a pale yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:8][C:9]([CH:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH3:13])=[N:10][CH:11]=1)=O)C.[BH4-].[Na+].CC#N>C(O)C>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:17]2[CH2:16][CH2:15][N:14]([CH:12]([C:9]3[N:8]=[C:7]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:6]([CH2:4][OH:3])=[CH:11][N:10]=3)[CH3:13])[CH2:19][CH2:18]2)(=[O:21])=[O:22])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc(C(C)N2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)nc1N1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(CO)c(N4CCCCC4)n3)CC2)cc1

Procedure:
To a solution of 2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-pyrimidine-5-carboxylic acid ethyl ester (104 mg, 0.2 mmol) in ethanol (1 mL) was added sodium borohydride (38 mg, 1.0 mmol) and the reaction mixture was heated to reflux for 1 day. The reaction was then partition between dichloromethane and saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo and then the residue was dissolved in DMSO (1 mL) and purified by LC-MS to yield the product. 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.62 (s, 2H), 4.53 (q, J=6.6 Hz, 1H), 3.93 (m, 7H), 3.25 (m, 8H), 1.77 (m, 6H), 1.67 (d, J=6.8 Hz, 3H); HPLC ret. time 2.49 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 476.1 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:26]5[N:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: Clc1ncccn1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Clc1ccc2c(c1)C1(CN3CCC(Nc4ncccn4)CC3)CC2c2ccccc21

Procedure:
4-amino-1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidine (0.500 g, 1.48 mmol, prepared as described in Example 7b) was heated to 100° C. for 5 hours in 1.5 mL N-methylpyrrolidinone with 2-chloropyrimidine (0.212 g, 1.85 mmol, commercial grade purified by extraction into petroleum ether) and triethylamine (0.300 g, 29.6 mmol) under a nitrogen atmosphere. Aqueous method (3 mL, 50% v/v) was added to the warm (50° C.) reaction mixture to give a white precipitate. The solid was collected by filtration and washed with fresh aqueous methanol (5 mL, 50% v/v) to give the title compound as a white solid. The solid was dissolved in methanolic hydrogen chloride, evaporated to dryness on a rotary evaporator, redissolved in a minimum volume of fresh methanol (2 mL) and added at a slow dropwise rate to rapidly stirring ethyl ether (80 mL) to precipitate the hydrochloride salt as a white solid (0.414 g, 0.99 mmol, 67%), mp 212°-214° C.; MS(CI) 417 (M+H); NMR (250 MHz, DMSO-d6): 10.17(br s, 1H), 8.38-8.33(m, 2H), 7.67(br m, 1H), 7.52-7.49(m, 1H, 7.38-7.31(m, 3H), 7.05-6.96(m, 3H), 6.70-6.63(m, 1H), 4.47(s, 1H), 4.35-4.29(m, 2H), 4.16(br m, 1H), 3.57-3.36(m, 4H), 2.76(m, 2H), 2.12-1.90 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[CH:15](=O)[CH2:16][CH3:17]>>[CH2:16]([CH:15]1[NH:10][C:5]2[C:6](=[CH:8][CH:9]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[N:7]2[CH:2]=[CH:3][CH:4]=[C:5]12)[CH3:17]
Reactant: CCC=O
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Product: CCC1Nc2cc(C(F)(F)F)ccc2-n2cccc21

Procedure:
4-Ethyl-7-trifluoromethyl -4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 4-trifluoromethyl-2-nitro aniline according to the sequence of Example 1 and 2, and the resulting oil treated with proprionaldehyde according tot he procedure of Example 3 to yield a light orange oil, which was used in the next step without further characterization.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]([F:24])([F:23])[F:22])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]([F:24])([F:22])[F:23])[CH2:7]1
Reactant: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl (2S)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate (1.40 g, 3.16 mmol, 1.00 equiv), dichloromethane (15 mL). Trifluoroacetic acid (3.80 g, 33.3 mmol, 9.40 equiv) was added at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 0.900 g (83% yield) of 4-(4-[[(3S)-3-methylpiperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl)morpholine as colorless oil. LCMS (ESI, m/z): 294 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:37][CH3:38])[C:21]([Cl:39])=[CH:20][N:19]=1>>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:37][CH3:38])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3C)ncc1Cl

Procedure:
The title compound was prepared in an analogous manner to the preparation of example 381 by combining 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield a light yellow solid (71%). LCMS: m/z=537.23 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H, J=8.8 Hz), 8.04 (s, 1H), 7.67 (dd, 1H, J=8.7, 2.4 Hz), 7.59 (s, 1H), 7.32 (d, 1H, J=2.0 Hz), 7.10 (d, 1H, J=8.6 Hz), 6.91 (s, 1H), 6.54 (d, 1H, J=2.3 Hz), 6.48 (dd, 1H, J=8.7, 2.2 Hz), 3.92 (s, 3H), 3.89 (m, 4H), 3.29 (s, 3H), 3.14 (m, 4H), 3.89 (m, 4H), 2.30 (m, 2H), 2.05 (m, 2H), 1.29 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OO.[O-:26]S([O-])=O.[Na+].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:11](=[O:26])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S([O-])[O-]
Reactant: COc1ccc(P(c2ccccc2)c2ccccc2)cc1OC
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(P(=O)(c2ccccc2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
da) 75 g of 3,4-dimethoxyphenyl-diphenylphosphine were taken up in 300 ml of methanol. 29.3 ml of 35% H2O2 solution were added dropwise to the suspension while cooling with an ice bath. The clear yellow solution was stirred at room temperature overnight, then treated with 100 ml of sat. Na2SO3 solution and 30 ml of 1N HCl and stirred for a further 1 hour. The resulting suspension was treated with 150 ml of water and the solution was evaporated on a rotary evaporator in order to remove the majority of the methanol. The precipitated yellow crystals were filtered off under suction, taken up in CH2Cl2, the solution was dried over MgSO4, filtered and evaporated. The residue was dissolved in 450 ml of hot ethyl acetate and the solution was treated with 450 ml of hexane. After standing overnight the crystallizate was filtered off under suction, washed with a small amount of hexane and dried at 0.1 mbar. There were obtained 54 g of (3,4-dimethoxyphenyl)diphenylphosphine oxide as a light beige powder. M.p. 154.5°-156° C.
Reaction SMILES: S1C=CC2C=C(C(=O)CC)C=CC1=2.[C:14]([O:18]C)(=[O:17])[CH2:15][SH:16].[Br:20][C:21]1[CH:22]=[CH:23][C:24](F)=[C:25]([CH:28]=1)[CH:26]=O>>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[S:16][C:15]([C:14]([OH:18])=[O:17])=[CH:26][C:25]=2[CH:28]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COC(=O)CS
Agent: CCC(=O)c1ccc2sccc2c1
Product: O=C(O)c1cc2cc(Br)ccc2s1
Yield: 95.1 %

Procedure:
In a similar manner to Example 9 Method A, 1-(benzo[b]thiophen-5-yl)propan-1-one was prepared starting from methyl thioglycolate (13.2 g) and 5-bromo-2-fluorobenzaldehyde (25.35 g) which were reacted together and the product hydrolysed to give 5-bromobenzo[b]thiophene-2-carboxylic acid (30.4 g), which was decarboxylated using copper and quinoline at 190° C. for 1.5 hours to give 5-bromobenzo[b]thiophene. This compound was reacted with magnesium and then with N-methoxy-N-methylpropionamide to give 1-(benzo[b]thiophen-5-yl)propan-1-one (1.3 g) as a cream solid which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[OH:20])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.[CH3:40][O-:41].[Na+]>CCOC(C)=O>[Cl:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[OH:20])[CH:8]=2)[N:3]=[C:2]([O:41][CH3:40])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[O-]
Reactant: Cn1cncc1C(O)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)c1ncccn1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1nc2ccc(C(O)(c3ncccn3)c3cncn3C)cc2c(Cl)c1-c1ccccc1

Procedure:
(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (156 mg, 0.337 mmol, Example 55), toluene (2 mL), and sodium methoxide (365 mg, 6.75 mmol) were combined in a round bottom flask equipped with a stirbar and condenser under an N2 atmosphere. The contents were heated to reflux and refluxed overnight. The reaction was cooled and the contents were transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI): mass calcd. for C25H20ClN5O2, 457.1; m/z found, 458.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 8.81 (d, J=4.9 Hz, 2H), 8.48 (d, J=1.8 Hz, 1H), 7.92-7.81 (m, 2H), 7.54-7.39 (m, 4H), 7.36-7.28 (m, 3H), 6.55 (s, 1H), 6.15 (s, 1H), 3.98 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]2[CH:28]([OH:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[CH:26]=3)[O:21][CH2:20]2)[CH:13]=1>>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C@H:19]2[C@@H:28]([OH:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=4)[CH:26]=3)[O:21][CH2:20]2)[CH:13]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: Oc1ccc2c(c1)C(O)C(Oc1cccnc1)CO2
Product: O[C@H]1c2cc(Oc3ccc4ccccc4n3)ccc2OC[C@H]1Oc1cccnc1

Procedure:
By the method of Example 1, 2-chloroquinoline and 3-(3-pyridyloxy)-4,6-chromandiol (EP appln. 312,295) were converted to present title product in like yield; mp 112°-114° C.; IR (CHCl3) 3563, 1620, 1603 cm-1.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13]>Cl>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([SH:1])=[CH:7][CH:6]=1)[CH3:13]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(S)cc1
Agent: Cl
Product: CCOC(=O)Cc1ccc(S)cc1

Procedure:
70 g G 4-mercapto-phenyl-acetic acid are heated at reflux for 30 minutes in 500 cc of 4 N hydrochloric acid in ethanol. The reaction mixture is then completely concentrated at reduced pressure. The oily residue is divided between ether and water, the ether phase is subsequently washed with a 10% sodium bicarbonate solution and water, is dried over sodium sulphate, and the solvent is removed by distillation. The crude 4-mercapto-phenyl-acetic acid ethyl ester, obtained as oily residue, may be purified by distillation; B.P. 103° at 0.4 mm of Hg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1)#[N:2].S(C1C=CC(C)=CC=1)(O[CH:14]1[CH2:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:20][C:16]1([CH3:21])[CH2:17][CH2:18][CH2:19][CH:14]([S:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1
Reactant: N#Cc1ccc(S)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC(C)(C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CCCC(Sc2ccc(C#N)cc2)C1
Temperature: 60 °C

Procedure:
To a solution of 4-cyanothiophenol (1 g, 7.4 mmol) in DMF (15 mL) add 3,3-dimethylcyclohexyl tosylate (2.06 g, 7.4 mmol) and potassium carbonate (3.06 g, 22.2 mmol), and warm to 60° C. for 18 h. Dilute the mixture with EtOAc (50 mL) and wash sequentially with water (3×50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as a clear oil that solidifies on standing (0.35 g, 20%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:41])[N:5]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH2:37])=[O:36])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3COCC[Si](C)(C)C)[CH3:13])=[N:7]2.OC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1>CO>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:41])[N:5]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH2:37])=[O:36])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][NH:19]3)[CH3:13])=[N:7]2
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C(N)=O)c3)c(=O)c12
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Solvent: CO
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(C(N)=O)c3)c(=O)c12

Procedure:
Compound 143 was treated with 4N HCL in MeOH for 1.5 hours using the procedure described for compound 121 (step D) to provide compound 142. m/z=441 (M+H). The structure of compound 0.142 is shown below.