Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=[O:20])[CH:18]=[CH2:19])([CH3:15])([CH3:14])[CH3:13].C(O)C.C(O)(=O)C>C(OCC)(=O)C>[C:12]([O:16][C:17](=[O:20])[CH2:18][CH2:19][S:9]([C:6]1[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of 4-bromophenylsulfinic acid sodium salt (729 mg), 2-propenoic acid t-butyl ester (439 μl), 95% ethanol (4 ml) and acetic acid (372 μl) was stirred for 12 hours at room temperature. Further, 2-propenoic acid t-butyl ester (2.20 ml) was added to the mixture and it was refluxed for 4 hours. The reaction mixture was diluted with ethyl acetate. The mixture was washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (872 mg) having the following physical data.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[N:4]([CH3:16])[C:3]1=[O:17])[C:12](=[O:15])[CH2:11][CH2:10][CH2:9]3.[C:18]([OH:21])(=[O:20])C.[H-].[Na+].O.O1CC[CH2:27][CH2:26]1>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[N:4]([CH3:16])[C:3]1=[O:17])[C:12](=[O:15])[CH:11]([C:18]([O:21][CH2:26][CH3:27])=[O:20])[CH2:10][CH2:9]3
Reactant: C1CCOC1
Reactant: CC(=O)O
Reactant: Cn1c(=O)n(C)c2cc3c(cc21)CCCC3=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CCc2cc3c(cc2C1=O)n(C)c(=O)n3C

Procedure:
60% Oily sodium hydride (6 g) was washed with n-hexane (2×30 ml), and the solvent was removed by decantation. Tetrahydrofuran (200 ml) and subsequently diethyl carbonate (9.8 g) were added thereto, and the mixture was refluxed gently. To the suspension was added dropwise a solution of 1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dione (10 g, 43.4 mmol) obtained in Reference Example 137 in hot tetrahydrofuran while maintaining refluxing. The mixture was refluxed for 18 hours, and allowed to cool, and then acetic acid (18 ml) was carefully added dropwise to decompose excessive sodium hydride. Further, water was added, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-diethyl ether to give the title compound as colorless crystals (7.0 g).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])C1C=CC=CC=1.C1CCCCC=1>CCO.[Pd]>[NH2:8][CH:9]([P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])[P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(OCC)C(N(Cc1ccccc1)Cc1ccccc1)P(=O)(OCC)OCC
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Yield: 119.5 %

Procedure:
Compound 1 (2.00 g, 4.14 mmol) was dissolved in EtOH (40 mL). To this solution was added palladium on carbon (10%, 1.5 g) and cyclohexene (2.5 mL, 24.7 mmol). The reaction mixture was refluxed under argon for 15 hours, filtered through celite and evaporated to give 2 as a slightly impure pale yellow oil (1.50 g, 119%), which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 1.35 (t, J=7.0, 12H), 3.58 (t, J=20.3, 1H), 3.65-3.90 (br s, 2H), 4.20-4.28 (m, 8H).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33]>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: Oc1ccccc1OCCCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Solvent: CC#N
Product: Oc1ccccc1OCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)C2
Product: [Br-]
Yield: 36.9 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (30.9 mg, 0.111 mmol) and 2-[(3-bromopropyl)oxy]phenol (47.9 mg, 0.207 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (20.9 mg, 37%). EI-MS m/z 430 (M+) Rt (1.70 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH2:10]([OH:15])[CH2:11][CH2:12][C:13]#[CH:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:13]([CH2:12][CH2:11][CH2:10][OH:15])=[CH:14][C:4]=2[CH:3]=1
Reactant: C#CCCCO
Reactant: Oc1ccc(Br)cc1I
Product: OCCCc1cc2cc(Br)ccc2o1

Procedure:
The product from Example 112A and 4-pentyn-1-ol is processed as described in Example 112B to provide the title compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CCN(C(C)C)C(C)C.Br[CH2:19][C:20]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC#N>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][CH2:19][CH:20]1[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: Nc1ccccc1N
Reactant: COC(=O)c1cccc(C(=O)CBr)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1cccc(C2CNc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,2-phenylenediamine (300 mg, 2.77 mmol) was dissolved in 2.7 mL MeCN. Hunig's Base (485 μl, 2.77 mmol) was added, followed by methyl 3-(2-bromoacetyl)benzoate (713 mg, 2.77 mmol). The resulting reaction mixture was stirred at room temperature for 30 minutes. Acetic acid (476 μl, 8.32 mmol) and sodium triacetoxyborohydride (1176 mg, 5.55 mmol) were added. The mixture was stirred at r.t. overnight. TLC indicated that the starting material was consumed, and the reaction was quenched with saturated ammonium chloride and extracted into DCM. The organic phase was dried with MgSO4, filtered, concentrated, and purified on a 100 g silica column with 0-30% EtOAc/hexanes gradient to give methyl 3-(1,2,3,4-tetrahydroquinoxalin-2-yl)benzoate.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26](Cl)=[C:21]3[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C>C(O)C>[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]([NH:2][CH:3]4[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]4)=[C:21]3[CH:20]=[CH:19]2)(=[O:16])=[O:17])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC1CCC(O)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
A mixture of 3-Amino-cyclopentanol hydrochloride (0.9 g, 5.9 mmol), 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (2.0 g, 5.9 mmol) and diisopropylethylamine (2.3 g, 17.7 mmol) in ethanol (100 mL) was stirred at 80° C. for 3 hours. The reaction mixture was purified by column chromatography (Hexanes/ethyl acetate=3:1) to give 2.6 g (76%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentanol; 1H NMR (400 MHz, CDCl3) δ: 9.56 (s, 1H), 9.54 (s, 1H), 8.19-8.16 (m, 2H), 7.62-7.56 (m, 4H), 6.82-6.81 (m, 1H), 4.56-4.50 (m, 2H), 2.25-1.96 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1.ClC1C=CC(C=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[O:30][C:31]=2[CH3:37])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=Cc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(Cl)cc3)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 108 b]) was reacted with 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (prepared by conversion of the 4-chloro-benzaldehyde into 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol in analogy to the sequence described in examples 21 a] to 21 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-2-ethoxy-propionic acid as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16](Cl)=[C:15](Cl)[CH:14]=2)[CH2:9]1)=[O:7].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(OCC)(=O)C>CO.C(OCC)(=O)C>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[C:13]1([C:10]2([CH2:21][CH2:22][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=3)[CH2:9]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCOCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using 2-[1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid morpholine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with ethyl acetate and then 10% methanol/ethyl acetate, the title compound. HRMS calculated for C38H47N3O6 : 642.354312. Found: 642.356150.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]1([CH:12]=O)[CH2:11][CH2:10]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:12][CH:9]1[CH2:11][CH2:10]1
Reactant: Nc1ccccc1Br
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1ccccc1NCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of 2-bromoaniline (1.720 g, 10.00 mmol), cyclopropanecarbaldehyde (0.374 mL, 5.00 mmol), and acetic acid (2.86 mL, 50.0 mmol) in dichloromethane (50 mL) was heated at 50° C. for 1 hour. The solution was cooled in an ice bath and sodium triacetoxyborohydride (2.119 g, 10.00 mmol) was added. This mixture was stirred for 2 hours while warming to ambient temperature and then partitioned between saturated sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate in heptane) to provide the title compound (1.05 g, 93% yield).
Reaction SMILES: [CH2:1]([CH:3]([C:9](O)([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>C(O)(=O)C.CS(O)(=O)=O.[Pd]>[CH2:1]([CH:3]([CH:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)C(O)(CC)c1ccc(OC)cc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Product: CCOC(=O)C(CC)C(CC)c1ccc(OC)cc1

Procedure:
10.7 g (0.038 mol) of ethyl 2-ethyl-3-hydroxy-3-(p-methoxyphenyl)pentanoate were hydrogenated in acetic acid (88 ml) solution in the presence of methanesulfonic acid (7 drops) by using 10% Pd-C as catalyst. The catalyst was filtered off and the solvent was evaporated. The product was dissolved in methylene chloride, washed with diluted potassium carbonate and water and dried. After evaporation of the solvent 9,5 g (97%) of the product as a mixture of erythro and threo diastereomers were obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:10]2[C:11](=[O:17])[NH:12][C:13]3=[CH:14][CH:15]=[CH:16][C:8](=[C:9]23)[O:7][CH2:6]1)=[O:4].[Br:24]N1C(=O)CCC1=O>C(#N)C.C(O)(=O)C.C(OCC)(=O)C>[Br:24][C:16]1[C:8]2[O:7][CH2:6][C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)([C:3]([NH:2][CH3:1])=[O:4])[N:10]3[C:11](=[O:17])[NH:12][C:13]([C:9]=23)=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)C1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNC(=O)C1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Reaction time: 1 h
Yield: 51.4 %

Procedure:
N-Methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (20 mg, 0.1 mmol) was dissolved in acetonitrile (3 mL) and acetic acid (2 mL), and cooled to 0° C., followed by addition of N-bromosuccinimide (20 mg, 0.1 mmol). The reaction mixture was stirred for 1 h and was then concentrated to give a crude residue. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7-bromo-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (0.020 g, 50%). LCMS calculated for C16H14BrN4O3 (M+H)+: m/z=389.1, 391.1. found: 388.9, 390.9.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]([NH:24][CH3:25])=[O:23])[N:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[F:36][CH2:37][CH2:38][CH2:39]Br>CN(C=O)C>[CH2:30]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]([N:24]([CH3:25])[CH2:39][CH2:38][CH2:37][F:36])=[O:23])[N:13]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1-c1nc(C(=O)NC)cc2ccccc12
Reactant: FCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1-c1nc(C(=O)N(C)CCCF)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 25.2 %

Procedure:
To a solution of 1-(2-tributylstannylphenyl)-N-methyl-3-isoquinoline-carboxamide (105 mg, 0.19 mmol) in DMF (5 mL) was added 60% NaH (65 mg, 1.61 mmol) in one portion. The mixture was stirred under Ar at room temperature for 40 min. Then, 3-fluoropropyl bromide (124 μl, 1.67 mmol) was added. After stirring under Ar at room temperature for 24 h, the mixture was quenched by adding H2O (9 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, 5-10% ethyl acetate/hexane, 0.1% Et3N), thereby affording an oil (29.3 mg, 25%), and starting material (62.5 mg). 1H NMR (CDCl3) d 0.32-0.68 (m, 6 H, SnCH2), 0.70 (t, J=7.2 Hz, 9 H, CH3), 0.95-1.32 (m, 12 H, CH2CH2), 2.15-2.28 (m, 2 H, CH2), 3.13 (d, J=11.1 Hz, 3 H, N-methyl), 3.58-3.85 (m, 2 H, N--CH2), 4.48 (qt, J=123.9, 47.4, 5.7 Hz, 2 H, CH2F), 7.42-7.62 (m, 4 H, aromatic), 7.65-7.80 (m, 2 H, aromatic), 7.91-8.15 (m, 3 H, aromatic). HRFABMS Calcd. for C32H46FN2O12OSn: 613.2599. Found: 613.2619.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:10]3([CH2:15][CH2:14][N:13]([C:16]4[S:17][C:18]([C:21]5[N:22]=[N:23][N:24]([CH2:26][C:27]([O:29]CC)=[O:28])[N:25]=5)=[CH:19][N:20]=4)[CH2:12][CH2:11]3)[CH:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C3C(=CC=CC=3)OC3(CCNCC3)C=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:10]3([CH2:11][CH2:12][N:13]([C:16]4[S:17][C:18]([C:21]5[N:22]=[N:23][N:24]([CH2:26][C:27]([OH:29])=[O:28])[N:25]=5)=[CH:19][N:20]=4)[CH2:14][CH2:15]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC4(C=C(c5ccc(F)cc5)c5ccccc5O4)CC3)s2)n1
Agent: Fc1ccc(C2=CC3(CCNCC3)Oc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CO
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC4(C=C(c5ccc(F)cc5)c5ccccc5O4)CC3)s2)n1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Step 3 Ethyl 2-(5-(2-(4-(4-fluorophenyl)spiro[chromene-2,4′-piperidine]-1′-yl)thiazol-5-yl)-2H-tetrazol-2-yl)acetate In a pressure vial, a mixture of 4-(4-fluorophenyl)spiro[chromene-2,4′-piperidine] (128 mg, 0.433 mmol), Intermediate 4 (175 mg, 0.550 mmol) and K2CO3 (127 mg, 0.919 mmol) were suspended in dry DME (2 mL). The vial was sealed and the mixture was stirred under N2 at an external temperature of 110° C. for 2 h. The reaction mixture was then cooled to room temperature, and diluted with DCM/methanol and concentrated under reduced pressure in the presence of silica gel. The resulting solid residue was purified by Combiflash™ chromatography (SiO2 (12 g), eluting with 3-10% EtOAc/hexanes) to afford the title compound as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1/[CH:18]=[CH:19]/[C:20]([Cl:22])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1/[CH:18]=[CH:19]/[C:20]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1c(F)cccc1F
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Fc1cccc(F)c1/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
To a solution of (E)-2,6-difluorocinnamic acid (331 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-2,6-difluorocinnamoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-2,6-difluorocinnamoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 369.80; mp: 204.5-206.5° C.; 1H-NMR (DMSO) δ: 8.82-8.77 (1H, m), 8.29-8.18 (1H, m), 8.00 (1H, d, J=16.5 Hz), 7.89-7.80 (2H, m), 7.74-7.66 (1H, m), 7.58-7.34 (4H, m), 7.39 (1H, d, J=16.5 Hz), 7.27-7.16 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:15]([F:26])([F:25])[F:14])[CH:21]=2)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N)c1[N+](=O)[O-]
Temperature: 150 °C
Yield: 19.3 %

Procedure:
A stirring suspension of 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (1.0 g, 5.04 mmol), 3-(trifluoromethyl)phenyl boronic acid (1148 mg, 6.04 mmol) and potassium carbonate (2.08 g, 15.1 mmol) in THF (16 ml) was degassed with nitrogen before the addition of palladium tetrakistriphenylphosphine (582 mg, 0.50 mmol). The resulting suspension was heated to 150° C. for 5 minutes using the ‘Creator’ microwave. The reaction mixture was filtered through celite and concentrated in vacuo. The residual brown oil was columned on silica gel using dichloromethane as eluant to give the title compound as a yellow solid (300 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>>[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([NH:17][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: Clc1ncnc2ccc(N3CCCC3)cc12
Reactant: Nc1ccc2[nH]ccc2c1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2cc(N3CCCC3)ccc2n1
Yield: 84 %

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-6-(1-pyrrolidinyl)quinazoline was reacted with 5-aminoindole to give 4-(5-indolylamino)-6-(1-pyrrolidinyl)quinazoline in 84% yield;
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@@H:20]([NH:45]C(OC(C)(C)C)=O)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(NCC2C3C(=CC=CC=3)N(CCCOC)C=2)CC1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@@H:20]([NH2:45])[CH2:19]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COCCCn1cc(CN(C(=O)[C@H]2C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Agent: COCCCn1cc(CNC2CC2)c2ccccc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCCn1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred, ice-cooled solution of (3R*,5S*)-3-tert-butoxycarbonylamino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (prepared from cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-amine analogously as described in Example 59A) (1.2 g, 1.7 mmol) in CH2Cl2 (8 ml), 2,6-lutidine (0.79 mL, 6.8 mmol) is added followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (0.92 mL, 5.1 mmol). The cooling bath is removed, and the mixture is stirred at RT for 2.5 h. The reaction mixture is diluted with CH2Cl2 and washed with saturated NH4Cl solution. The organic layer is dried over Na2SO4 and evaporated in vacuo to afford the title compound as a brownish solid, which is used without further purification for the next steps. MS: 607.5 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 6.05 min.