Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5])#[N:2].[OH-].[Na+].O>C(O)C>[C:1]([CH:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)Cc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC(Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Ethyl 2-cyano-3-(3-indolyl)propionate (350 mg, 1.45 mmol) (S. Masanori, et al., Heterocycles, 1981, 16: 941-9) was dissolved in ethanol (6 mL). 2N Sodium hydroxide solution (4 mL) was added and the reaction mixture was stirred at ambient temperature for 20 hours. Water (10 mL) was added and the ethanol was removed under reduced pressure. The pH of the aqueous solution was adjusted to approximately 1 with 6N hydrochloric acid solution and it was extracted with ethyl acetate. The ethyl acetate solution was concentrated in vacuo to give the title compound which was carried on to the next step without purification.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[N:15]=[C:16]([CH3:19])[S:17][CH:18]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][NH:31][C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.C(OCC)(=O)C>CS(C)=O.O>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[N:15]=[C:16]([CH3:19])[S:17][CH:18]=4)[C:12]=3[N:34]3[CH2:35][CH2:36][C@H:32]([NH:31][CH3:30])[CH2:33]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN[C@H]1CCNC1
Reactant: Cc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2F)cs1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN[C@H]1CCN(c2c(-c3csc(C)n3)c(C)c(C#N)c3nc(C4CC4)oc23)C1
Temperature: 90 °C
Reaction time: 6 h
Yield: 17.5 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1,3-benzoxazole-4-carbonitrile (I-80) (100 mg, 0.32 mmol) was dissolved in dimethyl sulfoxide (2 ml), triethylamine (112 μl, 0.80 mmol) and (3S)-3-methylaminopyrrolidine (44 μl, 0.42 mmol) were added, followed by stirring at 90° C. for 6 hours under nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated away and the resulting residue was subjected to preparative thin-layer silica gel column chromatography, eluted with a mixed solvent of chloroform/methanol (10:1, v/v) followed by recrystallization and purification with a mixed solvent of diethyl ether/ethyl acetate/n-hexane to obtain the entitled compound (22 mg, 17%) as a white solid.
Reaction SMILES: C[O:2][C:3]([NH:5][C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])=O>C1(C)C=CC=CC=1>[N:5]([C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])=[C:3]=[O:2]
Reactant: C=C(NC(=O)OC)C(=O)OC
Solvent: Cc1ccccc1
Product: C=C(N=C=O)C(=O)OC
Temperature: -78 °C
Yield: 50 %

Procedure:
The apparatus and procedure used in Example 6 are repeated except that the tube is filled with silica-alumina (Strem, 87% silica, 52.39 g after drying). A solution of methyl alpha-(methoxycarbonylamino)-acrylate (5.86 g, 0.37 mmol) in 10 ml toluene is passed down the column. Both traps are cooled to -78° C., and the contents are combined for analysis. 1H NMR of the reaction products (14.2 g including toluene) indicated a 90% conversion of starting material and a 50% yield of isocyanate.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:42]1[CH:43]=[CH:44][C:39]([CH2:38][CH2:37][NH:36][S:33]([C:29]2[CH:28]=[C:27]([NH:26][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=5)=[N:6][C:7]=34)=[O:13])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])=[CH:40][CH:41]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCCc2ccncc2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCCc2ccncc2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-pyridin-4-yl-ethyl)-benzenesulfonamide (example B.7) according to general procedure II. Yellow solid. MS (ISP) 615.3 [(M−H−]; mp 238° C.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[C:29]12([N:39]=[C:40]=[O:41])[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:40]([NH:39][C:29]23[CH2:38][CH:33]4[CH2:32][CH:31]([CH2:37][CH:35]([CH2:34]4)[CH2:36]2)[CH2:30]3)=[O:41])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N1CC(OC(c2ccc(F)cc2)c2ccccc2C(F)(F)F)C1
Yield: 93 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]azetidine hydrochloride (162) (200 mg, 0.55 mmol) in anhydrous DCM (5 mL) was added MP-carbonate (3.01 mmol/g; 550 mg, 1.65 mmol) and 1-adamantyl isocyanate (101 mg, 0.55 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (16 mL), then evaporated to afford the desired product as a white foam (257 mg, 92%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:10]=[CH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[C:5]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=Cc1ncccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ncccc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 74 %

Procedure:
To an oven dried 10 mL of a vial, was added 3-nitro-2-vinylpyridine (0.300 g, 2 mmol), 4-amino-1-Boc-piperidine (0.601 g, 3.00 mmol), and ethanol (5 ml). Triethylamine (0.843 ml, 6.00 mmol) was added and the vial was capped and heated at 90° C. for 24 hours. Solvents were removed from the mixture by roto-vap. Silica gel chromatography eluting 2M ammonia in methanol-dichloromethane afforded the title compound in 74% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.73 (dd, J=4.58, 1.53 Hz, 1 H) 8.19 (dd, J=8.24, 1.22 Hz, 1 H) 7.33 (dd, J=8.24, 4.58 Hz, 1 H) 3.95 (bs, 2 H) 3.30 (t, J=6.87 Hz, 2 H) 3.10 (t, J=6.71 Hz, 2 H) 2.78 (t, J=11.60 Hz, 2 H) 2.56-2.69 (m, 1 H) 1.76-1.84 (m, 2 H) 1.42 (s, 9 H) 1.13-1.27 (m, 2 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[CH2:33][CH2:32][CH2:31]3)[CH:27]=1)=O)C.[CH3:38][NH2:39]>CO>[CH3:38][NH:39][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[CH2:33][CH2:32][CH2:31]3)[CH:27]=1)=[O:3]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(C(=O)N(C)C)c3)ncc2c1=O
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(C(=O)N(C)C)c3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.2 mg, 0.010 mmol) was dissolved in MeOH (1 mL) and methylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 2.1 mg of 2-(3-dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.56 (br. S, 1H), 9.33 (s, 1H), 8.77 (s, 1H), 7.51 (dd, 1H, J=2.3 Hz, J=9.31 Hz), 7.34 (d, 1H, J=7.9 Hz), 7.11 (dd, 1H, J=1.7 Hz, J=7.8 Hz), 6.99 (br. S, 1H), 2.86-3.05 (m, 13H), 2.12-2.19 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H26N6O3: 482.21, Found: 483.2 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=2)=[CH:3][N:2]=1.[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:21]([C:18]3[CH:19]=[CH:20][C:15]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:16][CH:17]=3)=[O:22])=[CH:9][CH:8]=2)=[CH:3][N:2]=1
Reactant: NCc1ccc(-c2ccnnc2)cc1
Reactant: O=C(O)c1ccc(-c2ccccc2)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: CS(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(-c2ccnnc2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (4-(pyridazin-4-yl)phenyl)methanamine 1-3 (19 mg, 0.1 mmol), biphenyl-4-carboxylic acid 1-4 (20 mg, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (38 mg, 0.1 mmol) in DMF (0.5 mL) was added DIEA (0.052 mL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give N-(4-(pyridazin-4-yl)benzyl)biphenyl-4-carboxamide 1 as a white solid. MS m/z 366.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ9.59 (m, 1H), 9.21 (dd, 1H), 9.16 (t, 1H), 7.96 (m, 3H), 7.87 (d, 2H), 7.74 (d, 2H), 7.69 (m, 2H), 7.47-7.41 (m, 4H), 7.37 (m, 1H), 4.52 (d, 2H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH:15]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=3)[CH3:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([BH3-])#N.[Na+].C=O>C(#N)C>[CH3:35][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH:15]([C:17]2[CH:18]=[C:19]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=2)[CH3:16])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a suspension of (±)-3′-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (15 mg, 0.032 mmol) and sodium cyanoborohydride (10.2 mg, 0.16 mmol) in acetonitrile (1 mL) at 0° C. was added formalin (0.1 mL, 3.6 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and loaded onto an SCX cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 13 mg (84%) as a colorless film. 1H NMR (500 MHz, CDCl3) δ ppm 7.74 (m, 2H), 7.64 (s, 1H), 7.56 (m, 2H), 7.37 (s, 2H), 7.22-7.35 (m, 5H), 7.16 (m, 1H), 4.29 (q, J=6.4 Hz, 1H), 3.32 (d, J=8.9 Hz, 1H), 3.25 (d, J=8.9 Hz, 1H), 2.61 (m, 2H), 2.11-2.35 (m, 7H), 1.95-2.10 (m, 2H), 1.34 (m, 3H). Mass spec.: 479.30 (MH)+. Accurate mass spec.: m/z 479.2300 [MH]+, Δ=2.1 ppm.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6](C)=[CH:5][C:4]=1[S:10]([C:13]1[CH:14]=[C:15]([C:22]([O:24][CH3:25])=[O:23])[C:16]2[O:20][CH:19]=[CH:18][C:17]=2[CH:21]=1)(=[O:12])=[O:11].C1(S(C2C=C(C(OC)=O)C3OCCC=3C=2)(=O)=O)C=CC=CC=1>>[C:4]1([S:10]([C:13]2[CH:14]=[C:15]([C:22]([O:24][CH3:25])=[O:23])[C:16]3[O:20][CH:19]=[CH:18][C:17]=3[CH:21]=2)(=[O:12])=[O:11])[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(C)ccc2OC)cc2ccoc12
Agent: COC(=O)c1cc(S(=O)(=O)c2ccccc2)cc2c1OCC2
Product: COC(=O)c1cc(S(=O)(=O)c2ccccc2)cc2ccoc12

Procedure:
The title compound was prepared according to the procedure of Intermediate 67 starting from methyl 5-(phenylsulfonyl)-2,3-dihydro-1-benzofuran-7-carboxylate (198 mg, 0.6 mmol; obtained in Step 1). Yield: 80 mg (41%) after purification by preparative HPLC (System F; 40-70% MeCN). MS (ESI+) for C16H14O5S m/z 317 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([OH:26])=O.Cl.[CH3:28][O:29][C:30]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]2[C:31]=1[CH2:32][CH2:33][NH:34][CH2:35]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([N:34]1[CH2:33][CH2:32][C:31]2[C:36](=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:30]=2[O:29][CH3:28])[CH2:35]1)=[O:26]
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Reactant: COc1cc2c(c(OC)c1)CCNC2
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccc(F)cc13)C2
Yield: 34.3 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 106 (34.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.84 and 2.99 (2t, 2H), 3.48 (s, 1H), 3.53 and 4.03 (2t, 2H), 3.69-3.3.81 (m, 6H), 3.86-3.92 (m, 8H), 4.31 and 4.77 (2s, 2H), 6.35-6.50 (m, 2H), 7.66-7.85 (m, 3H), 8.02-8.05 (m, 1H), 8.23-8.28 (m, 1H); MS (ESI) m/z 534 ([M+H]+).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].[C:6]([SiH2:10][O:11][C:12]([CH3:23])([CH3:22])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=O)([CH3:9])([CH3:8])[CH3:7].[BH4-].[Na+]>CO>[C:6]([SiH2:10][O:11][C:12]([CH3:23])([CH3:22])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][NH:4][CH2:3][CH:2]([F:5])[F:1])([CH3:9])([CH3:7])[CH3:8]
Reactant: NCC(F)F
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(C=O)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CNCC(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
2,2-Difluoroethylamine (660 mg, 7.90 mmol) was added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzaldehyde (1.50 g, 5.27 mmol) in MeOH (53 mL). The mixture was heated to reflux for 4 h, and was allowed to cool down to rt. NaBH4 (300 mg, 7.90 mmol) was added carefully by portions, and the mixture was stirred for 1 h. The solvents were removed under reduced pressure, and the resulting oil was diluted with EtOAc. The mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-(2,2-difluoro-ethyl)-amine (1.86 g) as a clear crude oil that was used further directly. This crude material was dissolved in CH2Cl2 (53 mL), and DIPEA (2.7 mL, 15.6 mmol) was added, followed by Boc2O (1.70 g, 7.90 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with CH2Cl2 (50 mL), and washed with aq. 1M HCl, aq. sat. NaHCO3, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 5:95) yielded the title compound (2.27 g, 96%). LC-MS: tR=1.22 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][C:33]([CH3:39])([CH3:38])[C:34]2=O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.CCOC(C)=O>[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][C:33]([CH3:39])([CH3:38])/[C:34]/2=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:30][CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC1(C)Cc2ccc(OCc3ccccc3)cc2C1=O
Reactant: COC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C1/c2cc(OCc3ccccc3)ccc2CC1(C)C
Temperature: -78 °C
Yield: 45 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide (1.0 M in THF) (3.6 mL, 3.6 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (0.59 mL, 3.6 mmol) in THF (20 mL). The mixture was maintained at −78° C. for 7 minutes and then 6-(benzyloxy)-2,2-dimethyl-2,3-dihydroinden-1-one (8.3) (0.535 g, 2.0 mmol) was added in one portion. The resulting mixture was stirred at −78° C. and allowed to warm to room temperature overnight. The reaction mixture was then diluted with EtOAc (200 mL), washed with water and brine, and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:5 EtOAc/hexane) to give product 8.4 in 45% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2I)=[CH:5][CH:4]=1.C(N(CC)CC)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:21])[NH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CCNC(=O)c2ccccc2I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cc2c[nH]c(=O)c3ccccc23)cn1
Reaction time: 48 h

Procedure:
Under a N2 atmosphere, 2.04 g (5.17 mmol) of an (E/Z) mixture of 2-iodo-benzoic acid-[3-(6-methoxy-pyridin-3-yl)-allylamide], 1.53 g (5.17 mmol) of tetra-butylammonium chloride and 22 mg (0.1 mmol) of palladium diacetate are dissolved in 80 ml of DMF, then 1.8 ml (12.9 mmol) of triethylamine are added and stirring effected for 2 days at 110° C. Filtration is carried out, and the DMF is partially evaporated on a RE. The residue is dissolved with EtOAc and diluted Na2CO3 solution, the water phase separated and extraction effected twice more with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, methylene chloride/acetone 3:1), concentration by evaporation and stirring in petroleum ether yield 4-[(6-methoxy-pyridin-3-yl)-methyl]-2H-isoquinolin-1-one; m.p. 191° C.; HPLC(gradient20-100) tRet=7.9.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:26][O:27][CH3:28])=[N:14][N:15]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:16]=3[CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[N:36]=[N:37][N:38](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:39]=1>CO.ClCCl>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:26][O:27][CH3:28])=[N:14][N:15]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:16]=3[CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:39][N:38]=[N:37][N:36]=1
Reactant: CCCCc1c(Cc2ccc3oc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c(Br)c3c2)c(COC)nn1CC(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCCCc1c(Cc2ccc3oc(-c4ccccc4-c4nnn[nH]4)c(Br)c3c2)c(COC)nn1CC(F)(F)F

Procedure:
From a solution of the Intermediate 14b (210 mg) in methanol (3 ml) and dichloromethane (1 ml) with dl-1-camphor-sulphonic acid (52 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[C:33]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCC(CC)(c1ccc(NS(C)(=O)=O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(N(C)S(C)(=O)=O)c(C)c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of N-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-methanesulfonamide (230 mg, 0.5 mmol), triphenyl phosphine (197 mg, 0.75 mmol), MeOH (0.03 mL, 0.75 mmol), and THF (10 mL) is added diethylazodicarboxylate (0.12 mL, 0.75 mmol) and stirred overnight. The reaction is concentrated and chromatographed (0% to 25% EtOAc/Hex) to give the title compound (180 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:18][CH2:19][C:20](Cl)=[O:21]>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([NH:1][C:20](=[O:21])[CH:19]=[CH2:18])=[CH:7][N:6]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-Amino-2,4-dichloropyrimidine (Chempacific; 100 mg, 0.610 mmol) in THF (2 mL) was added triethylamine (170 μL, 1.22 mmol) followed by 3-Chloropropionyl Chloride (Aldrich; 64 mL, 0.671 mmol) The reaction was stirred at room temperature for 18 hrs.
Reaction SMILES: C[C:2]([CH3:24])([CH:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[NH:8][CH2:9][CH2:10][C:11]([O:13]C)=O)[C:3](OC)=O.[CH2:25]([Cl:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl>C(C(C)=O)C>[ClH:32].[CH2:25]([N:8]1[CH2:9][CH2:10][C:11](=[O:13])[C:2]([CH3:3])([CH3:24])[CH:7]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)CCNC(Cc1ccc(OC)cc1)C(C)(C)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: COc1ccc(CC2N(Cc3ccccc3)CCC(=O)C2(C)C)cc1
Reaction time: 35 h

Procedure:
A mixture of 24.5 g of crude dimethyl 2,2-dimethyl-3-(p-methoxybenzyl)-3,3'-iminodipropionate, 27 g of benzyl chloride, 23 g of potassium iodide, 40 g of potassium carbonate and 300 ml of methyl ethyl ketone is refluxed and stirred during 35 hours. The mixture is cooled and evaporated in vacuo whereupon the residue is treated with chloroform. Inorganic material is removed by filtration and the filtrate is concentrated in vacuo leaving a residue which is shaken with 300 ml of 4 N hydrochloric acid and 100 ml of petroleum ether in order to remove neutral products. After basification with aqueous ammonia, the N-benzyl-2,2-dimethyl-3-(p-methoxybenzyl)-3,3'-iminodipropionic acid dimethylester is extracted from the mixture by shaking with chloroform. It is obtained in nearly quantitative yield, and, without purification submitted to a Dieckmann cyclization using 5.2 g of sodium hydride (50% dispersion in oil) and 200 ml of dimethylformamide. Further processing is carried out according to the directions already described in preceding examples, giving the above-mentioned product which is recrystalized from ethanol/ether. Yield 35%. Melting point 161° - 162° C, with decomposition.