Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[S:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1.C1COCC1>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>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:36]3[CH:37]=[CH:38][S:34][CH:35]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)c1
Reactant: OB(O)c1ccsc1
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: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4ccsc4)cc23)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Azaindole 26 (33 mg, 0.00076 mol), Potassium carbonate (44 mg, 0.00032 mol), 3-thiophene boronic acid (20 mg, 0.0002 mol), THF (7 mL), water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.000004 mol) were added to a round bottom flask. The reaction mixture was stirred under nitrogen at 70° C. for overnight. The solvent was removed and the resulting residue was dissolved in EtOAc, washed with brine, dried over MgSO4 and concentrated. The desired product was purified by silica gel flash chromatography using a 90:10 Hexane/ETOAc solvent system. The product 27 was identified by LC/MS and H1-NMR. LRMS (ESI+): (M+H+)+436.5
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7]3[C:27]([C:28](=[O:29])[C:4]=2[C:3]=1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][C:25]1[C:12]2[S:13][C:14](Br)=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]=2[C:10](=[O:30])[C:9]=1[CH:8]=3.[CH2:39]([C:47]1[CH:51]=[C:50]([Sn](C)(C)C)[S:49][CH:48]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>[Pd]>[CH2:39]([C:47]1[CH:51]=[C:50]([C:14]2[S:13][C:12]3[C:25]4[C:9]([C:10](=[O:30])[C:11]=3[C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][C:7]2[C:5]3[S:6][C:2]([C:2]5[S:6][CH:5]=[C:4]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=5)=[C:3]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:4]=3[C:28](=[O:29])[C:27]=2[CH:26]=4)[S:49][CH:48]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCc1c(Br)sc2c1c(=O)c1cc3c(cc12)c(=O)c1c(CCCCCCCC)c(Br)sc13
Reactant: CCCCCCCCc1csc([Sn](C)(C)C)c1
Agent: [Pd]
Product: CCCCCCCCc1csc(-c2sc3c(c2CCCCCCCC)c(=O)c2cc4c(cc23)c(=O)c2c(CCCCCCCC)c(-c3cc(CCCCCCCC)cs3)sc24)c1
Yield: 72 %

Procedure:
This product is synthesised from 2,7-dibromo-3.8-dioctyl-4,9-dihydro-s-indaceno[1,2-b:5,6-b′]dithiophene-4,9-dione (FL128, 0.65 g, 0.96 mmol) and 3-octyl-5-trimethylstannylthiophene (2.5 eq.) according to the Stille palladium catalysed coupling method as described previously. After which, the product is purified on chromatography column (silica gel, hexane/CHCl3, 7:3) to give 0.62 g (72%) of a green-blue solid.
Reaction SMILES: [C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)(O)=[O:2].[NH3:25]>C1(C)C=CC=CC=1.O=S(Cl)Cl.CO>[C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)(=[O:2])[NH2:25]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C(=O)O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: N
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: C[C@]12CCC(=O)CC1[C@@H](C(N)=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 85 °C
Reaction time: 5.5 h

Procedure:
To a stirred suspension of 6α-carboxyandrostane-3,17-dione (II-aq, Prepn. 17, 600 mg) in dry toluene (12 mL), SOCl2 (623 μL) was added. After stirring 5.5 h at 85° C. the solution was cooled at 0° C. and 2M NH3 solution in MeOH (2.97 mL) was added. After stirring overnight at room temperature, the mixture was evaporated to dryness. The residue was treated with CH2Cl2 and H2O and extracted with CH2Cl2. The combined organic extracts were washed with 10% K2CO3 solution, brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 50/50) to give the title compound II-ar (90 mg, 15%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.27 (bs, 1H), 6.78 (bs, 1H), 2.50-0.72 (m, 21H), 1.00 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)C.O>[S:26]([O:17][CH2:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)(=[O:28])(=[O:27])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CCCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.87 g (20.0 mM) of 3-(1-tert-butoxycarbonyl-4-piperidyl)-1-propanol and 5.6 ml (40.0 mM) of triethylamine in 50 ml of diethyl ether was added 1.86 ml (24.0 mM) of methanesulfonyl chloride at 0° C. and the mixture was stirred at 0° C. for 30 minutes. This reaction mixture was then poured in iced water and extracted with ether. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4 and the solvent was distilled off under reduced pressure to provide 3-(1-tert-butoxycarbonyl-4-piperidyl)-1-propyl mesylate. To a solution of the above mesylate in 100 ml of N,N-dimethylformamide was added 3.70 g (20.0 mM) of potassium phthalimide and the mixture was heated at 100° C. for 90 minutes. After cooling to room temperature, this reaction mixture was poured in iced water and the resulting precipitate was collected by filtration, rinsed with water, and dried in vacuo to provide the title compound as white solid (20.24 g, 90%).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[OH:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[NH:13]2.O>O1CCCC1.CN(C)C=O>[O:18]=[C:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7][O:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[NH:13]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)OCCc1cccc2c1CC(=O)N2
Temperature: 80 °C
Yield: 15.9 %

Procedure:
Ethyl isocyanate (0.633 mL, 8 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (709 mg, 4 mmol) in tetrahydrofuran (8 mL) and dimethylforamide (2 mL) under nitrogen atmosphere. The mixture was heated at 80° C. for 48 hours. The reaction was cooled, poured into water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 158 mg (16%) of ethyl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[O:11]C)[C:6]#[N:7].[Cl-].[NH4+].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[NH:20][N:19]=[N:18][N:7]=2)[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[OH:11]
Reactant: COc1cc(C#N)cc([N+](=O)[O-])c1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nnn[nH]2)cc([N+](=O)[O-])c1O
Reaction time: 31 h

Procedure:
4.0 g of 3,4-dimethoxy-5-nitro-benzonitrile are dissolved in 50 ml of dimethylformamide, whereupon the solution is treated with 1.66 g of ammonium chloride and 2.02 g of sodium azide and stirred at 125° for 31 hours. After in each case 8 and 15 hours the same amounts of ammonium chloride and sodium azide are added thereto. After cooling the mixture is poured on to ice. The separated precipitate is filtered under suction, washed with water and dried. There is obtained 2-methoxy-6-nitro-4-(1H-tetrazol-5-yl)phenol in the form of orange crystals of m.p. >240° (dec.).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH:18]([C:24](O)=[O:25])[CH2:17]2.C(N(CC)CC)C.ClC(OCC)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O1CCCC1>[N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH:18]([C:24]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:25])[CH2:17]2
Reactant: CCN1CC(C(=O)O)Cc2cccc(CSc3nc4ccccc4[nH]3)c21
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CC(C(=O)N2CCOCC2)Cc2cccc(CSc3nc4ccccc4[nH]3)c21
Yield: 45.3 %

Procedure:
To a solution of 8-(2-benzimidazolyl)thiomethyl-1-ethyl-1,2,3,4-tetrahydroquinoline-3-carboxylic acid (1.3 g) in tetrahydrofuran (50 ml) were added dropwise triethylamine (0.4 g) and ethyl chloroformate (0.4 g) with stirring under ice-cooling and the mixture was stirred for 30 minutes. Moreover morpholine (0.4 g) was added dropwise thereto and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off and the resulting residue was dissolved in chloroform. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:dichloromethane-methanol (200:1)], and recrystallized from ethyl acetate-ethanol to give 8-(2-benzimidazolyl)thiomethyl-3-morpholinocarbonyl-1-ethyl-1,2,3,4-tetrahydroquinoline (0.7 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][NH2:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S1C2C=C(C(O)=O)C=CC=2N=[CH:13]1.Cl.S1C2C=CN=CC=2C=C1CN>>[S:1]1[C:5]2[CH:6]=[C:7]([CH:10]([NH2:11])[CH3:13])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NCc1ccc2ncsc2c1
Reactant: O=C(O)c1ccc2ncsc2c1
Agent: Cl
Agent: NCc1cc2cnccc2s1
Product: CC(N)c1ccc2ncsc2c1

Procedure:
Intermediate T′ was prepared from benzo[d]thiazole-6-carboxylic acid (T-1) following similar procedures for synthesizing intermediate D′-5 from D′-1, as described above, and intermediate D from D-4 as described above. MS (m/z): 179(M+1)+.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)=[CH:14][CH:15]=2)[C:10](=O)[NH:9][CH:8]=1>CC#N>[Cl:3][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[CH:12]=2)[C:7]([Cl:6])=[CH:8][N:9]=1
Reactant: N#Cc1cccc(-c2ccc3c(Cl)c[nH]c(=O)c3c2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1cccc(-c2ccc3c(Cl)cnc(Cl)c3c2)c1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
A solution of POCl3 (0.545 kg, 3.56 mol) in MeCN (0.76 L) was added to a suspension of 4-chloro-7-(3-cyanophenyl)isoquinolinone (0.50 kg, 1.78 mol) in boiling MeCN (4.25 L) under N2 over 1 hour. The mixture was heated at reflux overnight and then cooled to room temperature. The solid was collected by filtration, washed with MeCN (0.5 L) and dried in vacuo at 70° C. to give 1,4-dichloro-7-(3-cyanophenyl)isoquinoline (0.54 kg) as a creamy coloured solid which could be used without further drying or purification. The filtrate was slowly quenched with HCl (1N; 2.6 mL) which gave a second crop of 60 g of material which was filtered and washed with MeCN (0.5 L), which again could be used without further drying or purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH3:27])[C:20]3=[O:28])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]1[CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[N:32]=[CH:31]1.[F-].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.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>[CH3:27][O:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:19]([C:17]([NH:16][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:33]4[N:32]=[CH:31][N:30]([CH3:29])[CH:34]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[O:18])[C:20]1=[O:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Reactant: COCCN1CCN(C(=O)Nc2ccc(Oc3ccnc(Cl)c3)c(C)n2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCN1CCN(C(=O)Nc2ccc(Oc3ccnc(-c4cn(C)cn4)c3)c(C)n2)C1=O
Temperature: 105 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
A mixture of Example C5 (0.150 g, 0.370 mmol), N-methyl-4-(tributylstannyl)imidazole (0.178 g, 0.480 mmol) and Pd(PPh3)4 (0.021 g, 0.018 mmol) in toluene (4 mL) was sparged with Ar and heated at 105° C. overnight. The mixture was cooled to RT, treated with 10% KF and EtOAc, stirred for 2 h and the solids removed via filtration through diatomaceous earth. The filtrate was extracted with EtOAc (3×) and the combined organics were washed with 10% KF, then brine, dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN, sonicated, the solid removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was suspended in MeCN, sonicated and the solid collected via filtration. The filtrate was concentrated to dryness and further purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and combined with the above-isolated solid to afford 3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (61 mg, 36%). 1H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1 H), 8.35 (d, J=5.7 Hz, 1 H), 7.91 (d, J=8.8 Hz, 1H), 7.67 (d, J=1.3 Hz, 1 H), 7.64 (d, J=8.8 Hz, 1 H), 7.59 (d, J=1.3 Hz, 1 H), 7.16 (d, J=2.6 Hz, 1 H), 6.74 (dd, J=5.7, 2.6 Hz, 1 H), 3.84-3.78 (m, 2 H), 3.67 (s, 3 H), 3.54-3.47 (m, 4 H), 3.41-3.37 (m, 2 H), 3.26 (s, 3 H), 2.23 (s, 3H); MS (ESI) m/z: 452.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:41][C:42]1[CH:55]=[CH:54][C:45]([O:46][C:47]2[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=2)=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:41][C:42]1[CH:55]=[CH:54][C:45]([O:46][C:47]2[CH:53]=[CH:52][C:50]([NH:51][C:14]([C@@H:9]3[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[CH:49][CH:48]=2)=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Step (a) A flask was charged with (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.1 g, 9.1 mmol), HATU (3.80 g, 10.0 mmol), 4-(4-fluorophenoxy)aniline (1.85 g, 9.09 mmol), DIEA (4.8 mL, 27 mmol) and DMF (20 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then quenched with saturated sodium bicarbonate (aq., 20 mL). The mixture was extracted with ethyl acetate (60 mL) and the extract was washed with deionized water (30 mL) and then brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude (2S,4R)-tert-butyl 2-(4-(4-fluorophenoxy)phenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate, which was carried forward without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[C:11]([F:21])([F:20])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([C:36]2[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=2[C:38](Cl)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[F:20][C:11]1([F:21])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:8]([C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(C(=O)N2CCC(F)(F)C(=O)c3ccccc32)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCC(F)(F)C(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (200 mg) and 5 ml of pyridine were dissolved in 10 ml of methylene chloride, and 10 ml of a methylene chloride solution containing the o-phenylbenzoic acid chloride obtained above was added dropwise under ice-cooling. After 1 hour of stirring at room temperature, the solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with saturated sodium carbonate aqueous solution, 1N hydrochloric acid aqueous solution and saturated sodium chloride aqueous solution in that order. After drying on anhydrous magnesium sulfate and subsequent evaporation of the solvent under a reduced pressure, the resulting residue was applied to column chromatography, which was eluted with a mixed solvent of ethyl acetate and hexane (2:3, v/v) to obtain 283 mg of 4,4-difluoro-1-[4-(2-phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. This product was recrystallized from ethyl acetate-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][C:6]#[N:7].Br[CH2:13][CH2:14][CH2:15]Br.[H-].[Na+].CC(O)C>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([C:6]#[N:7])[CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3,4-dichlorobenzyl cyanide (25 g) and 1,3-dibromopropane (15 ml) in dry dimethyl sulphoxide (150 ml) was added dropwise under nitrogen to a stirred mixture of sodium hydride (7.5 g) dispersed in mineral oil (7.5 g) and dimethylsulphoxide (200 ml) at a temperature in the range 30° to 35° C. The mixture was stirred at room temperature for two hours and propan-2-ol (8 ml) and then water (110 ml) were added dropwise. The mixture was filtered through a diatomaceous earth sold under the Registered Trade Mark CELITE and the solid residue washed with ether. The ether layer was separated, washed with water, dried and evaporated. 1-(3,4-Dichlorophenyl)-1-cyclobutanecarbonitrile (b.p. 108°-120° C. at 0.15 Hg) was isolated by distillation. This method is a modification of that described by Butler and Pollatz (J. Org. Chem., Vol. 36, No. 9, 1971, p. 1308).
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([SH:20])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.[C:22](=O)([O-])[O-].[K+].[K+].CI.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([S:20][CH3:22])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CI
Product: CSc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
A mixture of 3.43 g (10 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol, 20 ml of absolute acetonitrile and 1.38 g of (10 mmol) of potassium carbonate is treated with 0.93 ml (15 mmol) of methyl iodide and the mixture is stirred at 40° C. for 5 hours. The reaction mixture is then treated with saturated, aqueous sodium carbonate solution and extracted repeatedly using ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. In this manner, 3.4 g (95% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-methylthio-1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of oil.
Reaction SMILES: [C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[C@H:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.CCN(C(C)C)C(C)C.[Si:51]([O:58][CH2:59][C@@H:60]1[C@@H:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:63][NH:62][CH2:61]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]>C(Cl)Cl>[Si:51]([O:58][CH2:59][C@@H:60]1[C@@H:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:63][N:62]([C@H:2]([CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[C:1]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:61]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H](O)C1CCCCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.4 %

Procedure:
A solution of 330 mg (1.3 mmol) of benzyl (S)-hexahydromandelate (from EXAMPLE 1, Step F) in 6.5 mL of CH2Cl2 at −78° C. was treated with 0.26 mL (1.5 mmol) of trifluoromethanesulfonic anhydride. The resulting mixture was stirred cold for 5 min and then treated with 0.30 mL (2.6 mmol) of 2,6-lutidine maintaining the internal temperature below −70° C. The resulting mixture was stirred cold for 15 min and then was treated with 0.46 mL (2.6 mmol) of DIEA. The resulting mixture was stirred cold for 15 min and then was treated with a solution of 300 mg (1.0 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (from EXAMPLE 1, Step E) in 1.0 mL CH2Cl2. The reaction was warmed to 0° C. and stirred for 5 h. The reaction was partitioned between 50 mL of ether and 25 ml of H2O and the layers were separated. The aqueous layer was extracted with 25 mL of ether. The combined organic phases were dried over MgSO4 and concentrated. Flash chromatography using 9:1 v/v hexanes/EtOAc as the eluant afforded 221 mg (31%) of the title compound: RF: 0.72 (4:1 v/v hexanes/EtOAc); 1H NMR (500 MHz) δ 0.002 (s, 3H), 0.005 (s, 3H), 0.87 (s, 9H), 0.98-1.80 (9H), 2.01-2.07 (m, 2H), 2.33-2.37 (m, 1H), 2.70-2.74 (m, 2H), 2.90 (q, J=8.0, 1H), 3.12 (t, J=8.0, 1H), 3.20-3.24 (m, 2H), 3.49 (dd, J=7.5, 8.5, 1H), 3.58 (dd, J=5.0, 10.0), 5.18 (s, 2H), 7.18-7.41 (10H).