Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:15]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[C:30]([F:32])[C:29](Br)=[CH:28][C:27]=2[F:34])=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH2:18][CH3:19].C(OC1(C2C=CC(CCCCC)=CC=2)C(F)=CC(C2C=CC=CC=2)=C(F)C1)CCCCC>>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:29]2[CH:28]=[C:27]([F:34])[C:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=3)=[CH:31][C:30]=2[F:32])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(B(O)O)cc1
Reactant: CCCCCc1ccc(-c2cc(F)c(Br)cc2F)cc1
Agent: CCCCCCOC1(c2ccc(CCCCC)cc2)CC(F)=C(c2ccccc2)C=C1F
Product: CCCCCc1ccc(-c2cc(F)c(-c3ccc(CCCCC)cc3)cc2F)cc1

Procedure:
The product from 2C is coupled with the product from 1F in an analogous manner as for 1G described to yield 4,4"-di-n-pentyl-2',5'-difluoro-p-terphenyl, K 65.0 N 86.0 I.
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].I[CH3:19].O>CN(C)C=O>[CH3:19][N:3]1[CH2:4][CH2:5][CH2:6][C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of (R)-tert-butyl 2-oxopiperidin-3-ylcarbamate (642 mg, 3.00 mmol) in N,N-dimethylformamide (3 mL) at room temperature was added sodium hydride (132 mg, 3.3 mmol). The reaction mixture stirred for 30 min, then iodomethane (206 μL, 3.3 mmol) was added and stirring was continued for 1 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (100 mL), using a continuous extractor apparatus overnight. The organic extract was evaporated to dryness under vacuum and the crude residue was purified by SiO2 chromatography (23 g, CH2Cl2/MeOH/NH4OH, 100:0:0 to 94:5.7:0.3) to give 310 mg (45%) of (R)-tert-butyl 1-methyl-2-oxopiperidin-3-ylcarbamate as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:31])[C@@H:12]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][O:14]CC1C=CC=CC=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[CH3:9][C:2]([NH:10][C:11](=[O:31])[C@@H:12]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][OH:14])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(NC(=O)[C@H](COCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(NC(=O)[C@H](CO)NC(=O)c1ccccc1)c1ccccc1
Yield: 89.3 %

Procedure:
2.0 g of (2S)-N-(α,α-dimethylbenzyl)-2-benzoylamino-3-benzyloxypropionamide (prepared as described in Example 5) was catalytically reduced with hydrogen gas in the presence of 0.4 g of 10% w/w palladium-on-carbon in a mixture of 4 ml of acetic acid and 60 ml of ethanol. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off. Recrystallization of the resulting residue from acetic acid and hexane gave 1.4 g of the title compound, melting at 152°-153° C.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:15]([OH:17])=O)[CH2:11][CH2:12][S:13][CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(NC(C(O)=O)C(C)C)(=O)C1C=CC=CC=1.Cl.ClC1C=CC(C2CCNCC2)=CC=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([C:15](=[O:17])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12][S:13][CH3:14])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: CSCCC(NC(=O)c1ccccc1)C(=O)O
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: Clc1ccc(C2CCNCC2)cc1
Product: CSCCC(NC(=O)c1ccccc1)C(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
Example 217 was prepared in a similar manner as described for the preparation of Example 208 with the exceptions that benzoyl-DL-methionine and 4-(4-chlorophenyl)-4-hydroxypiperidine were substituted for benzoyl-DL-valine and 4-(4-chlorophenyl)piperidine hydrochloride, respectively. MS found: (M+H)+=448.
Reaction SMILES: [OH:1][CH2:2][N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[C:4]1=[O:17].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[OH:1][CH2:2][N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[C:4]1=[O:17]
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)N(CO)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(CO)C1=O

Procedure:
The title compound is prepared from a mixture of 3,4-dihydro-2-(hydroxymethyl)-8-methyl-2H-pyrido[4,3-b]indol-1(5H)-one, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([N:23]2[CH2:27][CH2:26][N:25]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][N:13]=3)[C:24]2=[O:28])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1NCCN1c1ccccc1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Product: O=C1N(Cc2ccc(C#Cc3ccccc3)cn2)CCN1c1ccccc1

Procedure:
The title compound, light yellow solid, MS: m/e=354.3 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 1-phenyl-imidazolidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:35][O:36][CH3:37])[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][NH:16]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[N:13]([S:30]([O-:33])(=[O:32])=[O:31])[C:12]2=[O:34])=[O:9])[N:6]=1.[Na+].[H][H]>O.O1CCCC1.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:35][O:36][CH3:37])[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][NH2:16])[N:13]([S:30]([OH:33])(=[O:31])=[O:32])[C:12]2=[O:34])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1CNC(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN)c1csc(N)n1

Procedure:
In a mixture of 15 ml of water and 15 ml of tetrahydrofuran is dissolved 203 mg of sodium cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-(p-nitrobenzyloxycarbonylaminomethyl)-2-oxoazetidine-1-sulfonate (syn-isomer), followed by addition of 190 mg of 10% palladium-on-carbon. The mixture is stirred in a hydrogen atmosphere at room temperature for 3 hours. The catalyst is filtered off and the filtrate is washed with ethyl acetate and concentrated under reduced pressure. The residue is chromatographed on an Amberlite XAD-II column and lyophilized to give a colorless powder. The powder is rechromatographed on a Sephadex LH-20 column and lyophilized to give cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-aminomethyl-2-oxoazetidine-1-sulfonic acid (syn-isomer).
Reaction SMILES: CO.[Na].[CH3:4][SH:5].Br[C:7]([CH3:14])([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:8]>O>[CH3:4][S:5][C:7]([CH3:14])([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:8]
Reactant: CC(C)C(=O)C(C)(C)Br
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CO
Product: CSC(C)(C)C(=O)C(C)C

Procedure:
A solution of 200 ml. of methanol containing 9.2 g. (0.40 mole) sodium metal was cooled in an ice-bath and saturated with gaseous methyl mercaptan. To this was added 77.2 g. (0.40 mole) of 2-bromo-2,4-dimethylpentan-3-one at room temperature and the resulting mixture stirred for two hours. The reaction mixture was diluted with water, extracted with ethyl ether, the extracts washed with water, brine and dried over anhydrous sodium sulfate. The ether was evaporated and the residue distilled in vacuo to afford 50.4 g. of product, B.P. 76° (20 mm.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[NH4+].[H][H]>CN(C=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]1CCOC1
Agent: [Ni]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
100 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline are hydrogenated in 400 ml DMF in the presence of 33.1 g Raney nickel and 18.7 g ammonium chloride at 40° C., until the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is added dropwise to 1.2 l water. The suspension is stirred for 2.5 h at 0° C., suction filtered and washed with 500 ml of water. The residue is dried overnight at 55° C. under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:17])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].Br[CH2:21][CH:22]=[CH2:23]>CN(C)C=O.C(OCC)C>[CH2:23]([O:17][C:9]1([CH2:8][N:5]2[C:6]([CH3:7])=[C:2]([Br:1])[CH:3]=[N:4]2)[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: Cc1c(Br)cnn1CC1(O)CCCC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 157B (2.73 g) in N,N-dimethylformamide (20 mL) was added NaH (1.45 g) and the reaction mixture was stirred for 30 minutes at room temperature. 3-Bromoprop-1-ene (1.53 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether (75 mL), washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 1.5% to 15% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:14][C:15]1[C:23]2[O:22][CH:21]=[C:20]([CH:24]=O)[C:19]=2[CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[Br:14][C:15]1[C:23]2[O:22][CH:21]=[C:20]([CH2:24][N:11]3[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1coc2c(Br)cccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2coc3c(Br)cccc23)CC1
Reaction time: 12 h

Procedure:
To a flask charged with Boc-piperazine (130 mg, 0.70 mmol) and 7-bromo-1-benzofuran-3-carbaldehyde (141 mg, 0.63 mmol) was added NaBH(OAc)3 (761 mg, 2.80 mmol). The mixture was stirred at room temperture for 12 hours. Then the reaction was diluted with EtOAc (50 mL), washed with brine (15 mL), dried over Na2SO4 and concentrated. The residue was purified with prep-TLC to obtain the pure product tert-butyl 4-[(7-bromo-1-benzofuran-3-yl)methyl]piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[O:22][CH:23]([CH3:25])[CH3:24])=[N:6][CH:7]=1.Br[CH2:40][CH2:41][OH:42]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[C:10]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:40][CH2:41][OH:42])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: OCCBr
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(CCO)CC1
Temperature: 70 °C

Procedure:
5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (Example 7, 0.087 mmol) is dissolved in anhydrous DMF (1 mL). TEA (0.04 mL, 0.262 mmol, 3 equiv.) is added followed by 2-bromo-ethanol (0.019 mL, 0.262 mmol, 3 equiv.) dissolved in anhydrous DMF (0.7 mL). The reaction vessel is sealed and heated at 70° C. for 12 h. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous NaOH (5×), the organic layer is then dried over Na2SO4 and filtered. After concentration, the crude product is purified using preparative RP LC-MS to give 2-[4-(4-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-methyl-phenyl)-piperidin-1-yl]-ethanol (72) as a yellow powder: ESMS m/z 602.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Si]([N:23]=[N+:24]=[N-])(C)(C)C>CC#N>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:7]=1)=[N+:23]=[N-:24]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(N)cc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N=[N+]=[N-])cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Following the procedure of Moses and coworkers (K. Barral, A. D. Moorhouse, J. E. Moses, Org. Lett. 2007, 9, 1809-1811). N-(4-aminophenyl)-4-methylbenzene-1-sulfonamide (1.00 g, 3.81 mmol) was dissolved in anhydrous CH3CN (6 mL), and the resulting solution was placed under Ar(g) and cooled to 0° C. To this was added t-BuONO (0.68 mL, 5.71 mmol) followed by TMSN3 (0.60 mL, 4.57 mmol) dropwise. The resulting solution was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 10% EtOAc/hexanes, to give aryl azide 7 (1.02 g, 3.54 mmol, 93% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2.[C:22]1(=[O:28])[NH:26][C:25](=[O:27])[CH:24]=[CH:23]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH:24]2[C:25](=[O:27])[NH:26][C:22](=[O:28])[CH:23]2[C:18]2[C:17]3[CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH2:9]1
Reactant: O=[N+]([O-])c1ccc2[nH]c(C=Cc3ccccc3Cl)cc2c1
Reactant: O=C1C=CC(=O)N1
Product: O=C1NC(=O)C2C(c3ccccc3Cl)Cc3[nH]c4ccc([N+](=O)[O-])cc4c3C12
Yield: 74 %

Procedure:
Reaction of the diene (905) prepared as described in example 455 with maleimide using the procedure described in example 68 gave the adduct (917) (74%) as a dark solid which was immediately aromatised.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1>C(O)(C(F)(F)F)=O.CO>[Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C@@H:6]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C@@H:7]3[NH:8][C:9]=2[CH:10]=1
Reactant: Clc1cc2[nH]c3c(c2cc1Cl)CCNCC3
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Clc1cc2c(cc1Cl)[C@@H]1CCNCC[C@@H]1N2
Reaction time: 2.5 h
Yield: 34 %

Procedure:
A solution of 8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.40 g, 1.6 mmol) in TFA (4.0 mL) was cooled to 0° C., then a freshly prepared solution of Na(CN)BH3 (0.49 g, 7.8 mmol) in MeOH (1.5 mL) was added dropwise. The ice bath was removed after the addition was complete. After 2.5 h, the reaction was diluted with H2O, made basic with 50% aqueous NaOH, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography and prep HPLC to give 0.14 g (36%) of the title compound as pale orange solid. 1H NMR (d-CHCl3) δ 7.00, 6.58, 4.22, 3.81, 3.58, 3.14-2.98, 2.79, 2.07-1.87; IR (drift) 3201, 3170, 3149, 3031, 2927, 2852, 2838, 2750, 1608, 1483, 1450, 1365, 1273, 832, 660 cm−1; HRMS (FAB) calcd for C12H14Cl2N2+H 257.0612, found 257.0614.
Reaction SMILES: C([CH:3]1[CH:29]=[C:28](C)[CH2:27][CH:26](C)[CH2:25][CH:24](OC)[CH:23]2[O:34][C:19](O)([CH:20](C)[CH2:21][CH:22]2OC)[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8](C(C)=CC2CCC(OC)C(O)C2)[CH:7](C)[CH2:6][CH2:5][C:4]1=[O:55])C.C(N(S(F)(F)F)CC)C.F>C(Cl)Cl>[CH:19]12[O:34][CH:23]([CH2:22][CH2:21][CH2:20]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:3][C:4](=[O:55])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10](=[O:41])[CH:11]1[N:16]([CH2:15][CH2:14][CH2:13][CH2:12]1)[C:17](=[O:40])[C:18]2=[O:39]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: CCN(CC)S(F)(F)F
Agent: F
Solvent: ClCCl
Product: O=C1CC=CCCCCC2CCCC(O2)C(=O)C(=O)N2CCCCC2C(=O)OCCCC1

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(3"-hydroxy-4"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in MeCl2 is treated with diethylaminosulfur triflouride and the resultant product is treated with 48% aqueous hydrofluoric acid as in Example 63 yields 17-ethyl-1-hydroxy-12-[2'-(3"-fluoro-4"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetrmethyl-11,28,dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:39][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(C(F)(F)F)cc1)N1CCN(C2CCC2)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (49%).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.Cl.N1C=CC=CC=1.[CH2:18]([C:22]1[O:26][N:25]=[C:24]([CH2:27][NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][C:30]=2[NH2:39])[CH:23]=1)[CH2:19][CH2:20][CH3:21]>C(#N)C>[CH2:18]([C:22]1[O:26][N:25]=[C:24]([CH2:27][N:28]2[C:29]3[C:38]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[N:32]=[CH:31][C:30]=3[N:39]=[CH:1]2)[CH:23]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1cc(CNc2c(N)cnc3ccccc23)no1
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCc1cc(Cn2cnc3cnc4ccccc4c32)no1
Yield: 86.5 %

Procedure:
Triethyl orthoformate (0.80 mL, 4.80 mmol) and pyridine hydrochloride (0.092 g, 0.80 mmol) were sequentially added to a solution of N4-[(5-butylisoxazol-3-yl)methyl]quinoline-3,4-diamine (1.19 g, 4.00 mmol) in acetonitrile (100 mL), and the solution was heated gently at reflux overnight. An analysis by HPLC indicated the presence of starting material, and additional triethyl orthoformate and pyridine hydrochloride were added. The solution was heated at reflux for an additional 24 hours. The solvents were removed under reduced pressure, and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was separated and extracted with dichloromethane, and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with 3% to 8% methanol in dichloromethane) to provide 1.06 g of 1-[(5-butylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline as an orange solid.
Reaction SMILES: C(=O)([O-])N.C[O:6][C:7](=[O:24])[CH2:8][C:9]1[C:10]([CH3:23])=[N:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:13]=1[CH3:14].C(N(C(C)C)CC)(C)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>ClCCl>[CH2:38]([O:37][C:35]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:13]([CH3:14])=[C:9]([CH2:8][C:7]([OH:6])=[O:24])[C:10]([CH3:23])=[N:11]2)=[CH:17][CH:18]=1)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Agent: NC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(Cc2ccc(NC(=O)OCc3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Carbamate formation: To a solution of [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.3, 70 mg, 0.26 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (55 μL, 0.32 mmol) and benzyl chloroformate (55 μL, 0.39 mmol). The reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered over Alox B, eluting with 10% methanol in dichloromethane. Saponification: After removing the volatiles under reduced pressure, the remaining residue was dissolved, in methanol (1 mL) and treated with aqueous NaOH solution (4 M, 0.2 mL). The mixture was neutralized with aqueous HCl and purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:1])=[CH:10][CH:9]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(C=O)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of n-butyllithium (4 mL, 2,5 M solution in Hexane, 10 mmol) (Aldrich) in ether (30 mL) was added methyltriphenylphosphonium bromide (3.57 g, 10 mmol) (Aldrich) over a period of 5 min. The reaction mixture was stirred for 4 h at room temperature. To the resulting orange solution was added 4-methoxybenzaldehyde (1.34 mL, 10 mmol) (Aldrich) dropwise. The solution became colorless, and a white precipitate separated. The mixture was then heated to reflux and immediately allowed to cool to room temperature. The precipitate was removed by filtration. The precipitate was washed with ether and the combined ethereal filtrates were washed with water until neutral and then dried over anhydrous MgSO4. The solvent was removed, and the residue was used in the next reaction without further purification.