Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[B:32]([O-])([O-:34])[O-:33]>C1COCC1.CCCCCC>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[B:32]([OH:34])[OH:33])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: [O-]B([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1ccc2ccccc21
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (11.0 g; 78 mmols) in THF (170 ml), at -78° C. and under nitrogen, a 1.6M solution of BuLi (56.1 ml; 89.7 mmols) in hexane is added slowly in order to maintain the temperature below -65° C. The mixture is stirred at -75° C. for 10 min and is then warmed to 0° C. within 30 min. After cooling again to -78° C., a solution of 1-tert-butoxycarbonylindole (15.6 g; 72 mmols) in THF (300 ml) is added, keeping the temperature below -65° C. The mixture is stirred 1 hour at -75° C. and a solution of trimrthyl borate (7.5 g; 72 mmols) in THF (200 ml) is added dropwise. The reaction is allowed to warm up to room temperature overnight. A 0.25N solution of Hcl (200 ml) is added and the THF is removed under vacuum. The residue is extracted with ethyl ether (3×150 ml) and the combined organic phases are washed with water (2×100 ml) and dried over sodium sulphate. The solution is then concentrated, cooled to 0° C. and filtered to obtain crystalline (1-tert-butoxycarbonylindol-2-yl)boronic acid (6.95 g; 26.6 mmols). Yield: 37%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:34])[N:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.O1CCOCC1.[NH2:45][CH2:46][CH2:47][C:48]#[N:49].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:37])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:27]3[CH2:32][CH2:31][CH:30]([NH:49][CH2:48][CH2:47][C:46]#[N:45])[CH2:29][CH2:28]3)=[O:34])[N:9]=2)[CH:7]=1
Reactant: O=C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: N#CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: N#CCCNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-1H-pyrazol-4-yl}-amide.dioxane (36 g, 57.0 mmol) in DCM (500 mL) was treated with 3-amino-propionitrile (5.0 mL, 68.4 mmol) and acetic acid (50 mL). The mixture was cooled in an ice bath before the addition of sodium triacetoxyborohydride (18.1 g, 85.4 mmol) portionwise. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was diluted with methanol and loaded onto a pad of Isolute® SCX-2 which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The basic fractions were combined and evaporated to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piperidin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-amide as a pale brown solid (31.1 g, 91%). LCMS (Method 3) [M+H]+=598.2, RT=2.25 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.84 (s, 1H), 8.78 (dd, 1H, J=1.6, 6.9 Hz), 8.69 (s, 1H), 8.58-8.55 (m, 1H), 8.40 (s, 1H), 7.68 (d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7 Hz), 7.28 (d, 1H, J=8.7 Hz), 7.28 (s, 1H), 7.00 (dd, 1H, J=4.2, 6.9 Hz), 6.50 (t, 1H, J=74.1 Hz), 5.08 (d, 1H, J=15.4 Hz), 5.02 (d, 1H, J=15.5 Hz), 4.37 (d, 1H, J=13.4 Hz), 3.88 (d, 1H, J=13.4 Hz), 3.22-3.12 (m, 1H), 3.02 (t, 1H, J=6.4 Hz), 2.98-2.86 (m, 2H), 2.82-2.72 (m, 1H), 2.52-2.46 (m, 2H), 1.96-1.83 (m, 2H), 1.36-1.20 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][C:31]([NH:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[C:30]([S:51][CH2:52][CH2:53]O)[CH:29]=1>O1CCCC1.C(OCC)(=O)C>[F:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][C:31]([NH:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[C:30]([S:51][CH2:52][CH2:53][I:25])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])c(F)cc2SCCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])c(F)cc2SCCI)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.6 %

Procedure:
To a stirred solution of triphenylphosphine (668 mg, 2.55 mmol) and imidazole (0.693 mL, 5.09 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was added iodine (732 mg, 2.88 mmol). The resulting mixture was stirred at 0° C. for 5 minutes. To this mixture was then added tert-butyl 4-(4-fluoro-2-(2-hydroxyethylthio)-5-nitrophenylamino)piperidine-1-carboxylate (705 mg, 1.697 mmol) as a solution in tetrahydrofuran (5 mL), and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate, water, saturated sodium thiosulfate, and brine. The organic phase was dried, filtered, concentrated, and then chromatographed in 1:9 ethyl acetate:hexanes to afford the desired product (398 mg, 44.6%). 1H NMR (DMSO-d6) δ 7.53 (d, J=11.7 Hz, 1H), 7.27 (d, J=6.6 Hz, 1H), 5.10 (d, J=8.1 Hz, 1H), 3.96-3.85 (m, 2H), 3.64-3.52 (m, 1H), 3.50-3.41 (m, 2H), 3.39-3.32 (m, 2H), 2.99-2.81 (m, 2H), 1.91-1.81 (m, 2H), 1.48-1.32 (m, 11H); ESI-MS (m.z, %): 470 (100), 426 (81).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[Cl:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:13](=[O:14])[CH2:12][CH2:11][Cl:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C(Cl)CCCl
Reactant: Cc1ccc(N)cc1C
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)CCCl)cc1C
Temperature: 25 °C

Procedure:
3,4-Dimethylaniline (25.5 grams), β-chloropropionyl chloride (20 grams) and benzene (100 ml) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is stirred at reflux for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is washed with aqueous sodium bicarbonate, dilute hydrochloric acid and water. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered and stripped of benzene under reduced pressure to yield the desired product N-(3,4-dimethylphenyl)-β-chloropropionamide as the residue.
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1.[Cl:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([NH2:37])=[C:32]([CH3:38])[CH:31]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:37][C:33]3[C:34]([CH3:36])=[CH:35][C:30]([Cl:29])=[CH:31][C:32]=3[CH3:38])=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1
Reactant: Cc1cc(Cl)cc(C)c1N
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(C)c1NC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2)c([N+](=O)[O-])c1

Procedure:
The product of Example 162b (300 mg, 0.6197 mmol) and 4-Chloro-2,6-dimethyl-phenylamine (119 mg, 0.6197 mmol) were combined in toluene (10 mL) and reacted as in Example 162c to give the title compound that was used without further manipulation.
Reaction SMILES: C1(CCCC(O)=O)C2=C3C(C4C5C(=CC=CC2=5)C=CC=4)=CC=CC3=CC=1.C[O:28][C:29](=[O:58])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:39]=[CH:40][C:41]2[C:42]3[CH:43]=[CH:44][CH:45]=[C:46]4[C:57]=3[C:50]([C:51]3[C:56]=2[C:55]=1[CH:54]=[CH:53][CH:52]=3)=[CH:49][CH:48]=[CH:47]4)=O>>[CH:40]1[C:41]2=[C:56]3[C:51]([C:50]4[C:57]5[C:46](=[CH:45][CH:44]=[CH:43][C:42]2=5)[CH:47]=[CH:48][CH:49]=4)=[CH:52][CH:53]=[CH:54][C:55]3=[C:38]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]([OH:58])=[O:28])[CH:39]=1
Reactant: COC(=O)CCCCCCC(=O)c1ccc2c3cccc4cccc(c5cccc1c52)c43
Agent: O=C(O)CCCc1ccc2cccc3c4cccc5cccc(c1c23)c54
Product: O=C(O)CCCCCCCc1ccc2c3cccc4cccc(c5cccc1c52)c43

Procedure:
The synthesis and isolation was accomplished under identical conditions as described for perylenebutanoic acid starting from 7-(3-perylenoyl)heptanoic acid methyl ester yielding 60.0% perylenyloctanoic acid. Rf 0.63 (system 3). 1H-NMR (CDCl3/CD3OD, 9:1) (δ, ppm): 1.25-1.50 (m, 6H, 3(CH2)), 1.59 (m, 2H, 3-CH2), 1.72 (m, 2H, 7-CH2), 2.26 (dt, 2H, Ja,b 1.79 Hz, J2,3 7.45 Hz, 2-CH2), 2.97 (t, 2H, J7,8 7.72 Hz, 8-CH2), 7.28 (d, 1H, J 8.0 Hz, Ar), 7.43 (m, 3H, Ar), 7.59 (d, 1H, J 3.42 Hz, Ar), 7.63 (d, 1H, J 3.42 Hz, Ar), 7.83 (d, 1H, J 8.54 Hz, Ar), 8.10-8.22 (m, 4H, Ar).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=1
Reactant: NCCN1CCOCC1
Reactant: Clc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Product: Clc1ccc(-c2nc(Cl)cc(NCCN3CCOCC3)n2)cc1

Procedure:
Employing the procedure of Example VII, 7.0 g. of 4,6-dichloro-2-(p-chlorophenyl)-pyrimidine and 30 ml. of N-(β-aminoethyl)-morpholine is reacted to produce 8.9 g. of product. Recrystallization from n-heptane affords 4-chloro-2-(4-chlorophenyl)-6-[2-(morpholino)ethylamino]-pyrimidine, m.p. 127°-129°C.
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:20][C:21]1[C:22]([NH2:45])=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([CH:39]=1)[C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]1)=[O:27].CC(C)N=C=NC(C)C>>[F:1][C:2]1[C:15]([NH:16][C:17]2[NH:20][C:21]3[C:22]([N:45]=2)=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([C:26](=[O:27])[NH:28][C@H:29]2[CH2:30][CH2:31][C@H:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]2)[CH:39]=3)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCC(F)F)nc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1F
Agent: CC(C)N=C=NC(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3nc(OCC(F)F)c(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)cc3[nH]2)c1F

Procedure:
The title compound is prepared from N-(2-fluoro-4-chloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (55 mg, 0.18 mmol) and 5,6 diamino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (70 mg, 0.18 mmol) with DIC in analogy to examples 8a/8b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([Cl:16])=[O:13]
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)Cl)c(Cl)c1

Procedure:
160 g of 2-chloro-4-methoxyphenylacetic acid are suspended in 210 ml of toluene, and the suspension is stirred together with 96 ml of thionyl chloride at 80° C. until the evolution of gas has ceased. The volatile components are stripped off, and the residue is distilled. 90 g of an orange oil are obtained (thin-film evaporator 170° C., 0.08 mbar).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][CH:21]=3)=[CH2:15])[CH:5]=[CH:4][C:3]1=2.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=3)[C:22]([O:24][CH3:25])=[O:23])[CH3:15])[CH:5]=[CH:4][C:3]1=2
Reactant: [H][H]
Reactant: C=C(c1cccc(C(=O)OC)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of methyl 3-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)vinyl]phenylcarboxylate (1.2 g, 3.45 mmol) in ethyl acetate, in the presence of palladium-on-charcoal (0.3 g) at a pressure of 6 bar of hydrogen, is stirred at room temperature for 4 h. The mixture is filtered through Celite and then concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[CH2:25][O:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:11][C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][CH:9]=3)[NH:6][C:5]([CH3:31])=[CH:4]4)=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1C(C)=O
Yield: 46.5 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 11, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline (160 mg, 0.38 mmol) was reacted with acetyl chloride (32 μl, 0.46 mmol). The crude product was purified by column chromatography eluting with methanol/methylene chloride (2/98) to give 7-[(2R)-1-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (82 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]CC)=[O:16])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]3[CH2:12][CH2:13][CH2:14]3)[C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cc(Br)cc2c1ccn2C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)cc2c1ccn2C1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of ethyl 6-bromo-1-cyclobutyl-1H-indole-4-carboxylate (0.3 g, 0.973 mmol) (crude residue from above) in MeOH (8 mL) and THF (2 mL) was added 3M NaOH (1.298 mL, 3.89 mmol). The reaction was stirred at RT for 16 h, at which time the volatiles were removed in vacuo. The residue was diluted with water and slowly acidified with 1N HCl to pH 3-4. The solids were filtered and dried on hivac for 16 h to give 6-bromo-1-cyclobutyl-1H-indole-4-carboxylic acid (0.21 g, 0.535 mmol, 55.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.89 (m, 2H) 2.34-2.46 (m, 2H) 3.84 (s, 1H) 5.08 (t, J=8.21 Hz, 1H) 6.99 (d, J=3.03 Hz, 1H) 7.75-7.79 (m, 1H) 7.81 (d, J=3.03 Hz, 1H) 8.01-8.05 (m, 1H) 13.03 (br. s., 1H). MS(ES) [M+H]+ 294.1.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:26]=[O:27]>O1CCCC1>[CH2:1]([CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([CH:26]=[O:27])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CCC(Cc1ccccc1)C2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCC(Cc1ccccc1)C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-Benzyl-6-bromo-1,2,3,4-tetrahydronaphthalene (1.5 g, 0.005 mol) was dissolved in 30 ml tetrahydro-furan and cooled to -78° C. under dry N2. Butyl lithium (2.32 ml of 2.14 M in hexane, 0.005 mol) was added and the mixture stirred at -70° C. for 1 hour. Dimethyl-formamide (0.39 ml, 0.005 mol) was then added dropwise and the mixture stirred at -70° C. for 2 hours, allowed to warmed toward room temperature for 0.5 hour, poured slowly into 38 ml of ice cold 1N HCl and extracted 2×50 ml ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and stripped in vacuo to yield title product as an oil, 1.26 g; tlc Rf 0.6 (4:1 hexane:ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[S:33][C:34]([CH:38]=O)=[C:35]([CH3:37])[CH:36]=2)=[CH:4][N:3]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[S:33][C:34]([CH2:38][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[C:35]([CH3:37])[CH:36]=2)=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: COc1cc(-c2csc3c(-c4cc(C)c(C=O)s4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(-c4cc(C)c(CN5CCOCC5)s4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-{4-[4-amino-7-(5-formyl-4-methylthien-2-yl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (70.0 mg, 0.127 mmol) and morpholine (44.2 μL, 0.507 mmol) were reacted according to General Procedure B followed by HPLC purification to give the title compound as a light yellow powder. (3.2 mg, 0.0051 mmol): LCMS (Conditions a): MH−=622, RT=4.73 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.06 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 7.58 (dd, J=8.4, 0.80 Hz, 1H), 7.34 (m, 1H), 7.32 (m, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.20 (s, 1H), 7.12-7.16 (m, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H), 5.69 (br, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.63 (s, 2H), 3.60 (t, J=4.6 Hz, 4H), 2.46 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [NH:1]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N:7][N:6]=1)[C:2]([NH2:4])=[S:3].O=[C:16]([CH3:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.N>>[CH3:28][C:16]1[N:4]=[C:2]([NH:1][C:5]2[S:9][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N:7][N:6]=2)[S:3][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([S:24](=[O:26])(=[O:25])[NH2:27])=[CH:22][CH:23]=1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Reactant: NC(=S)Nc1nnc(CCC(=O)O)s1
Agent: N
Product: Cc1nc(Nc2nnc(CCC(=O)O)s2)sc1-c1ccc(S(N)(=O)=O)cc1

Procedure:
The titled compound is prepared from 3-(5-thioureido-[1,3,4]thiadiazol-2-yl)-propionic acid (56b) and from 4-(2-oxo-propyl)-benzenesulfonyl chloride (prepared as described in European patent specification EP 91749 A2) following procedures described for Example 1 using ammonia to prepare the sulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:28][S:29]SC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH3:15])[CH2:9][N:10]2[C:14]([S:29][CH3:28])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: CSSC
Reactant: C[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ncnn1C[Si](C)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
A solution of 1.5 g (0.005 mol) of bis(4-fluorophenyl)methyl(1H-1,2,4-triazol-1-ylmethyl)silane in 10 mL of THF was treated with n-butyllithium as described in Example 1. To this solution was added 0.63 mL (0.007 mol) of dimethyl disulfide. The reaction mixture was allowed to warm to 0°, stirred 30 minutes, then poured into 1:1 ether/hexanes, washed with 7% aqueous NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. The crude product was flash chromatographed (5% ether/methylene chloride) to give 1.4 g of the title compound as a clear oil: nD 1.5750; ir (neat) 3030 (w), 2935 (w), 1587, 1496, 1230, 1160, 1106, 1035, 822 cm-1 ; nmr (CDCl3) δ 0.7 (3H, s), 2.6 (3H, s), 4.0 (2H, s), 7.1 (4H, m), 7.5 (4H, m), 7.8 (1 H, s).
Reaction SMILES: [Mg].[CH3:2][O:3][CH2:4]Cl.[CH:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1>O1CCCC1>[CH3:2][O:3][CH2:4][C:11]1([OH:21])[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH2:14][CH2:15][C:16]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]1=2
Reactant: COCCl
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: [Mg]
Solvent: C1CCOC1
Product: COCC1(O)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of chloromethyl methyl ether (40.2 g, 0.5 mole, freshly distilled) in dry tetrahydrofuran (80 ml) is prepared, and about 5 ml of that solution are added to a stirred mixture of magnesium turnings (12.0 g, 0.5 g - atom) and mercuric chloride (500 mg) in tetrahydrofuran (20 ml) until an exothermic reaction ensues. The flask is cooled to 0°± 10° and the remainder of the chloromethyl methyl ether solution is added dropwise with thorough agitation. After completion of addition a solution of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (56.1 g 0.25 mole) in tetrahydrofuran is added dropwise. The reaction mixture is stirred overnight at room temperature and the complex is hydrolyzed with ice-cold ammonium chloride solution. The aqueous layer is extracted with ether (3 × 100 ml) and the combined extracts are washed with sodium chloride solution, dried and evaporated under reduced pressure to give 10,11-dihydro-5-methoxymethyl-5H-dibenzo[a,d]cyclohepten-5-ol as an oil with b.p. 143°- 144° C/0.05 mm, γmaxfilm : 3500 cm-1, 2820 cm-1.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:8][CH2:9][C@H:10]([O:21][CH3:22])[CH2:11][S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])C=CC=CC=1.Cl>C(O)C>[CH3:22][O:21][C@H:10]([CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:9][OH:8]
Reactant: COc1ccccc1SC[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Agent: Cl
Solvent: CCO
Product: COc1ccccc1SC[C@H](CO)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.3 %

Procedure:
35.8 g (0.076 mol) of 1-(3-triphenylmethyloxy-2-(S)-methoxypropylthio)-2-methoxybenzene (XIII-1) and 150 ml of a solution of hydrochloric acid (2.5N) in ethanol are introduced into a round-bottomed flask kept under an inert atmosphere. The mixture is stirred at ambient temperature for 4 hours. The white precipitate formed is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate=90:10). 13.4 g (0.058 mol) of the title compound (XIV-1) are recovered in the form of an orange oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[C:12]([CH:20]2[S:24][CH2:23][CH2:22][S:21]2)[CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].O.[OH-].[Li+].Cl>C1COCC1.O>[S:21]1[CH2:22][CH2:23][S:24][CH:20]1[C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[CH2:16][C:17]([OH:19])=[O:18])[CH2:9][C@@H:4]([C:3]([OH:25])=[O:2])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1ccc(CC(=O)O)c(C2SCCS2)c1)NC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(CC(=O)O)c(C2SCCS2)c1)C(=O)O
Reaction time: 0.75 h

Procedure:
To 3-(1,3-dithiolan-2-yl)-4(carboxymethyl)-N-acetyl-L-phenylalanine methyl ester (0.22 g, 0.57 mmol) in THF (10 mL) at 0° C. was added lithium hydroxide monohydrate (0.025 g, 0.60 mmol, 1 mL water). The mixture was stirred for 45 min, diluted with water, made acidic with 1 N HCl, and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a glassy solid which was homogeneous by RP HPLC (0.18 g, 86%). MS [M−H]− 368.