Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH:9]([C:12]#[N:13])[C:10]#[N:11])[CH:4]=1.O.[NH2:15][NH2:16]>CCO>[CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]2[C:10]([NH2:11])=[N:15][NH:16][C:12]=2[NH2:13])[CH:4]=1
Reactant: NN
Reactant: CSc1cc(C(C#N)C#N)ncn1
Solvent: O
Solvent: CCO
Product: CSc1cc(-c2c(N)n[nH]c2N)ncn1

Procedure:
2-(6-(methylthio)pyrimidin-4-yl)malononitrile (11.4 g, 0.06 mol) was suspended in 150 mL EtOH and hydrazine hydrate (3 mL, 0.06 mol) was added. The reaction mixture was heated to reflux for 3 days. The reaction mixture was concentrated to a solid which was suspended in ethyl acetate (100 mL), and filtered. This solid was dried to give the product, 10.4 g, 46.8 mmol, 78%, ca. 80% pure).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[C:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:13]([CH3:26])[C:14]([C:24]#[N:25])=[C:15]2[C:19]=1[O:18][C:17]([C:20](O)([CH3:22])[CH3:21])=[N:16]2.C(=O)([O-])O.[Na+]>ClCCl>[F:10][C:11]1[C:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:13]([CH3:26])[C:14]([C:24]#[N:25])=[C:15]2[C:19]=1[O:18][C:17]([C:20]([F:7])([CH3:22])[CH3:21])=[N:16]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)O)nc2c1C#N
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)F)nc2c1C#N
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.8 %

Procedure:
Under nitrogen atmosphere, diethylaminosulfur trifluoride (293 μl, 2.24 mmol) was dropwise added at 0° C. to a dichloromethane (5 ml) solution of 7-fluoro-2-(1-hydroxy-1-methylethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-112) (139 mg, 448 μmol), followed by stirring at room temperature for 14 hours. At 0° C., an aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, then the mixture liquid was extracted with chloroform. Next, the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=5:1, v/v) to obtain the entitled compound (134 mg, 96%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:10]([Br:12])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1Br)C(=O)CC2
Reaction time: 1 h

Procedure:
A solution of 6-aminoindanone (12 g, 81.6 mmol) in N,N-dimethylformamide (220 ml) is treated with N-bromosuccinimide (14.5 g, 81.6 mmol) in portions over a period of one hour and stirred for one hour. Evaporation of the solvent and water/dichloromethane workup followed by purification by chromatography with EtOAc/hexane (1:3) as eluent gives the product 6-amino-7-bromoindanone; LC/MS: 226/228 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=1)=[O:8]
Reactant: COc1ccc2sc(C(=O)Cl)c(Cl)c2c1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a 0° C. solution of 3-chloro-5-methoxybenzo[b]thiophene-2-carbonyl chloride (500 mg, 1.9 mmol) in 20 mL of THF is added methyl p-aminobenzoate (318 mg, 2.1 mmol) followed by triethylamine (293 μL, 2.1 mmol). The reaction mixture is allowed to warm to room temperature and stirring is continued overnight. The mixture is partitioned between ethyl acetate and 1N HCl, then washed with 1N NaOH, saturated NaHCO3, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane provides 225 mg of methyl 4-[[[3-chloro-5-methoxybenzo[b]thien-2yl]carbonyl]amino]benzoate; mp=205°-206° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[C:4]([N:6](CC)[CH2:7][CH3:8])=[O:5].C(N)C>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1N
Agent: CCN
Product: CCNC(=O)c1cc(Br)ccc1N
Yield: 70 %

Procedure:
Prepared analogously to Compound 3D replacing diethylamine with ethylamine to afford 1.41 g of the title product (70%). 1H NMR (400 MHz, CD3OD) δ 7.55 (d, J=2.3 Hz, 1H), 7.25 (dd, J=2.4, 8.7 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 3.32-3.38 (m, 2H), 1.20 (t, J=7.3 Hz, 3H). MS (ESI): m/z 243.33 [M+H]+. UPLC: tR=0.98 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:23]([O:25]CC)=[O:24])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH:20]([CH3:22])[CH3:21])=[C:4]([CH:28]([CH3:30])[CH3:29])[CH:3]=1.[Li+].[OH-]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:23]([OH:25])=[O:24])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH:20]([CH3:22])[CH3:21])=[C:4]([CH:28]([CH3:30])[CH3:29])[CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2C(C)C)c(-c2ccc(Cl)cc2C(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc(Cl)ccc1-c1cc(C(=O)O)sc1-c1ccc(Cl)cc1C(C)C
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of ethyl 4,5-bis(4-chloro-2-isopropylphenyl)thiophene-2-carboxylate (280 mg, 0.61 mmol) in THF (3 mL) and MeOH (3 mL) was added a solution of LiOH (72 mg, 3.0 mmol) in water (2 mL). The reaction was stirred at rt until complete, and then concentrated. The residue was re-dissolved in 20 mL of water and acidified with 1N aq. HCl to pH 2. The white precipitate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by recrystallization in a mixture solvent of ethyl acetate and hexane to afford 0.24 g (91%) of product as a white solid, 1H NMR (CDCl3, 500 MHz) δ 7.78 (s, 1H), 7.23 (d, J=2.15 Hz, 1H), 7.22 (d, J=1.88 Hz, 1H), 7.13-7.07 (m, 2H), 7.03 (dd, J1=8.23 Hz, J2=2.20 Hz, 1H), 6.89 (d, J=8.26 Hz, 1H), 2.95 (m, 2H), 1.04 (d, J—4.94 Hz, 6H), 0.98 (d, J=6.95 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 167.13, 149.87, 149.06, 146.58, 139.45, 137.21, 135.53, 134.39, 132.79, 131.84, 131.57, 131.14, 129.01, 126.43, 126.28, 125.86, 125.77, 30.27, 30.23, 23.93.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:16](=O)[CH3:17])[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH3:2].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:17])[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH3:2]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCOc1cc(C(C)=O)cnc1OCC(F)(F)F
Product: CCOc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)F
Yield: 93 %

Procedure:
The title compound is prepared in 93% yield (0.75 g, colorless oil) from 1-(5-ethoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.58 g, 2.19 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:21]([O:28][C:29](=[O:46])[N:30]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41](Br)[N:40]=1)[CH2:31][C:32]([NH:34][CH2:35][CH2:36][OH:37])=[O:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:46])[N:30]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([NH:1][C:2]2[S:3][C:4]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=3[F:20])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[N:40]=1)[CH2:31][C:32]([NH:34][CH2:35][CH2:36][OH:37])=[O:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=C(CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1)NCCO
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN(CC(=O)NCCO)C(=O)OCc4ccccc4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (50 mg, 0.17 mmol) and benzyl[(6-bromopyridin-2-yl)methyl]{2-[(2-hydroxyethyl)amino]-2-oxoethyl}carbamate (110 mg, 0.26 mmol) as starting materials.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])([O:19][CH2:20][CH3:21])[CH2:15][CH:14]=1)=O)([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([O:8][CH2:9][CH2:10][NH:12][C:13]2[CH:14]=[CH:15][C:16]([N+:22]([O-:24])=[O:23])([O:19][CH2:20][CH3:21])[CH2:17][CH:18]=2)[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC1([N+](=O)[O-])C=CC(NC(=O)COc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)=CC1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC1([N+](=O)[O-])C=CC(NCCOc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)=CC1

Procedure:
1.92 g (4.5 mmol) of 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]-N-(4-nitrophenetyl)acetamide (synthesis intermediate of compound 47) is introduced into 80 ml of anhydrous THF in a flask, under an argon atmosphere. A solution of 13.45 ml (13.45 mmol) of BH3 in THF is added to the reaction mixture and the mixture is agitated while heating at reflux for 4 hours 30 minutes. At the end of the reaction, 10 ml of MeOH is added and heating is maintained for a further 30 minutes. The reaction mixture is then concentrated under vacuum, the residue is taken up in 30 ml of a MeOH/HCl 3N mixture (2/1) and the mixture is taken to reflux for another hour. The reaction mixture is returned to 22° C., diluted with 50 ml of CH2Cl2 and 2M aqueous soda is added until a basic pH is obtained. After decantation, the organic phase is washed successively with 20 ml of water and 20 ml of brine, dried over sodium sulphate, filtered and concentrated under vacuum. The expected product is purified by chromatography on a silica column (eluent: CH2Cl2/EtOH: 25/1). Pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:15][NH:16][O:17][CH3:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNOC
Reactant: O=C(O)CCc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a solution of 3-(3,4-dichlorophenyl)propanoic acid (0.50 g, 2.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.27 g, 2.7 mmol) in DCM (5 mL) was added EDCI (0.57 g, 3.0 mmol), HOBt (0.35 g, 2.3 mmol) and TEA (0.39 mL, 2.8 mmol). The reaction mixture was stirred at rt for 18 h, concentrated and the residue was purified by ISCO chromatography (EtOAc/Hexanes 0-100% over 20 min, column 40 g, flow rate 40 mL/min) to give Intermediate 15A (569 mg, 2.17 mmol, 95.0% yield) as a clear oil. HPLC/MS (Method R) RT=1.76 min, [M+1]+ 262.1.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]12[CH2:15][CH2:14][CH2:13][C:11]3[C:12]1=[C:7]([CH:8]=[CH:9][CH:10]=3)[NH:6][C:5]2=[O:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]23[CH2:15][CH2:14][CH2:13][C:11]4[C:12]2=[C:7]([CH:8]=[CH:9][CH:10]=4)[NH:6][C:5]3=[O:16])[CH2:27][CH2:26]1
Reactant: O=C1Nc2cccc3c2C1(CCBr)CCC3
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCC23CCCc4cccc(c42)NC3=O)CC1
Yield: 32.2 %

Procedure:
2a-(2-Bromoethyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (140 mg, 0.5 mmol), 4-(2-methoxyphenyl)piperazine (148 mg, 0.77 mmol) and potassium carbonate (138 mg, 1 mmol) were stirred in anhydrous N,N-dimethylformamide (5 ml) at room temperature for 2 hours. The reaction solution was mixed with ethyl acetate (50 ml) and water (50 ml). The ethyl acetate layer was washed with water and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 63 mg of the title compound (32% in yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:24]=[C:23](C(Cl)(Cl)Cl)[N:22]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[N:30]=3)[C:21]=2[CH:36]=1>CN(C)C=O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:24]=[C:23]([O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]3)[N:22]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[N:30]=3)[C:21]=2[CH:36]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: CC1(C)OCC(CO)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(COc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.5 %

Procedure:
A mixture of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (800 mg, 6.05 mmol), cesium carbonate (1.7 g, 5.22 mmol) and 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol) in N,N-dimethylformamide (4 mL) was stirred for 12 hr at room temperature. The reaction mixture was quenched with 20 mL of water and the precipitate was collected by filtration. The solid was dried in a vacuum oven to afford 385 mg (75%) of 4-[6-bromo-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.40 (d, J=5.2 Hz, 2H), 7.40 (s, 2H), 7.21 (d, J=6.0 Hz, 1H), 5.28 (s, 2H), 4.77-4.60 (m, 3H), 4.22-4.20 (m, 1H), 3.96-3.92 (m, 1H), 1.49 (s, 3H), 1.42 (s, 3H); LC-MS: m/z=+420 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.CN(C=O)C>[Si:28]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([Cl:8])[C:18]=1[N+:19]([O-:21])=[O:20])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylamine (83 mL, 0.60 mol) was added to a solution of 4-(2-chloro-3-nitroquinolin-4-ylamino)butan-1-ol (44.34 g, 149.9 mmol). A solution of tert-butyldimethylsilyl chloride (100 g of a 50% w/w solution in toluene, 0.33 mol) in DMF (60 mL) was slowly added, and the reaction was then stirred at room temperature of five hours. Additional tert-butyldimethylsilyl chloride (50 g of a 50% w/w solution in toluene) was added, and the reaction was stirred at room temperature for three days. Additional tert-butyldimethylsilyl chloride (100 g of a 50% w/w solution in toluene, 0.33 mol) was added, and the reaction was stirred at room temperature for three hours. Finally, additional triethylamine (83 mL, 0.60 mol) and tert-butyldimethylsilyl chloride (100 g of a 50% w/w solution in toluene, 0.33 mol) were added, and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was filtered to remove a solid, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (250 mL), and the resulting solution was washed sequentially with 5% w/w aqueous ammonium chloride (3×150 mL), saturated aqueous sodium bicarbonate (2×150 mL), and brine (150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was further dried under vacuum and passed through a layer of silica gel (eluting with dichloromethane) to provide 56.04 g of N-[4-(tert-butyldimethylsilanyloxy)butyl]-2-chloro-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24]CC)=[O:23].O>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]([OH:24])=[O:23])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CCCCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
2-n-Butyl benzimidazole (3.00 g, 17.22 mmol) was mixed with powdered potassium carbonate (2.62 g, 19 mmol) and diluted with 25 mL dimethylformamide. To this was added ethyl bromoacetate (18.94 mmol). The reaction mixture was stirred at ambient temperature overnight and poured into 150 mL of water. The resulting crystals were filtered, and recrystallized from hexane to give 2.26 g (50%) of a solid; mp 70°-71° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[N:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2cc(Br)ccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1Cc2cc(Br)ccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A stirring mixture of 87E (0.60 g, 1.76 mmol), K2CO3 (0.49 g, 3.52 mmol), and benzyl bromide (0.36 g, 2.11 mmol) in acetone (15 mL) was heated to reflux under argon for 16 h. The mixture was then cooled to RT and the solvent was evaporated under vacuum. The resulting residue was partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried (Na2SO4), and evaporated. The resulting crude product was chromatographed on silica gel eluted with 10-20% EtOAc in hexane (step-wise gradient) to obtain the title compound (0.72 g) as a solid.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]1([C:17]2[C:26]([CH:27]([OH:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:41])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:43])([CH3:42])[O:22]3)[CH2:16][CH2:15][CH2:14][CH:13]=1.CO>O1CCCC1>[CH:12]1([C:17]2[C:26]([CH:27]([OH:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:40])[CH3:41])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:42])([CH3:43])[O:22]3)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)c1cc2c(c(C3=CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(C3CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
155 μl (872 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 4.9 mg (33 μmol) of (1R,2S)-1-aminoindan-2-ol in 5.0 ml of tetrahydrofuran, and the mixture is stirred for 30 min. A solution of 100 mg (218 μmol) of 5-cyclopent-1-en-1-yl-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 36A) in 5.0 ml of tetrahydrofuran is then, very slowly, added dropwise, and the mixture is stirred for 4 h. Methanol is then added, and the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The crude product is purified by preparative HPLC (method 1). In addition to the title compound, the compounds described as Preparation Examples 22 and 23 are also isolated (for yield and analytical data see there).
Reaction SMILES: [Na].[CH2:2](Br)[CH3:3].[CH:5]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>N>[CH2:2]([C:5]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:3]
Reactant: N#CC1CCCCCCC1
Reactant: CCBr
Agent: N
Agent: [Na]
Product: CCC1(C#N)CCCCCCC1

Procedure:
Sodium (3.7 g, 0.16 mole) was added to liquid ammonia (300 ml.) at 35° C. A catalytic amount of ferric nitrate was then added. After the solution had become grey in colour, ethyl bromide (17.4 g, 0.16 mole) and cyclooctyl cyanide (20.0 g, 0.14 mole) were added very slowly. The liquid ammonia was then allowed to evaporate over a period of 20 hours. Benzene and then water were added to the residue. The benzene layer was dried (MgSO4) and distilled to give 1-ethylcyclooctyl cyanide, bp. 130-132°/17 mm.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1.[CH3:18][Sn:19](Cl)([CH3:21])[CH3:20]>O1CCCC1>[CH3:6][O:7][C:8]1[C:9]([Sn:19]([CH3:21])([CH3:20])[CH3:18])=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=1
Reactant: C[Sn](C)(C)Cl
Reactant: COc1ccc(C(F)(F)F)nc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)nc1[Sn](C)(C)C
Temperature: 25 °C
Yield: 23 %

Procedure:
A solution of t-butyllithium (1.7M in pentane; 8.5 ml, 14.45 mmol) was added dropwise to a stirred solution of 3-methoxy-6-trifluoromethylpyridine (1.57 g, 8.87 mmol) in dry tetrahydrofuran (20 ml) at −78° C. over 5 min. After stirring for 10 min at −78° C. a solution of trimethyltin chloride in tetrahydrofuran (18 ml, 1 M in THF, 18 mmol) was added over 5 min. The reaction mixture was allowed to warm up to room temperature over 5 hour and then quenched with water (50 ml) and extraxted with hexane (3×30 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (100 g, hexane:diethyl ether 0-10%) to afford 3-methoxy-6-trifluoromethyl-2-trimethystannylpyridine (0.7 g, 23%) H1 NMR δ(250 MHz, CDCl3): 7.50 (1H, d, J 8.7 Hz), 7.02 (1H, d, J 8.7 Hz), 3.85 (3H, s), 0.35 (9H, s); and afford 3-methoxy-6-trifluoromethyl-4-trimethylstannylpyridine (1.7 g, 57%) H1 NMR δ(250 MHz, CDCl3): 8.38 (1H, s), 7.65 (1H, s), 3.95 (3H, s) 0.35 (9H, s).