Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.[OH-].[K+].CCO.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO>[CH2:21]([C:11]1[C:12](=[O:15])[NH:13][N:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C2=NNC(=O)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc(Cc3ccccc3)c(=O)[nH]n2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
6-(4-methoxy-phenyl)-4,5-dihydro-2H-pyridazin-3-one (1.65 g, 7.5 mmol) in 15 mL of EtOH was heated to 80° C. as 20 mL of 4% of KOH/EtOH solution was added dropwise. After 5 min., benzaldehyde (1.0 eq. 0.76 mL) was added and the mixture stirred at 80° C. for 2 h. The reaction was cooled to rt., poured into ice-H2O (75 mL) and the resulting solid was collected and crystallized from EtOH to give 1.67 g (76%) of intermediate 4-benzyl-6-(4-methoxy-phenyl)-2H-pyridazin-3-one: MS m/z 293 (M+H). This intermediate was used to prepare examples 45 and example 46.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][CH2:15][C:10]2=[N:9][N:8]=1.C(N(CC)C(C)C)(C)C.[CH3:25][Si:26]([CH3:41])([CH3:40])[CH2:27][CH2:28][O:29][C:30](ON1C(=O)CCC1=O)=[O:31]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][N:14]([C:30]([O:29][CH2:28][CH2:27][Si:26]([CH3:41])([CH3:40])[CH3:25])=[O:31])[CH2:15][C:10]2=[N:9][N:8]=1
Reactant: c1cnc(-c2nnc3n2CCNC3)cn1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOC(=O)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of 3-(pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 5.0 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.9 mmol) in DMF (15 mL) was added 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (1.5 g, 5.9 mmol). Stirred for 18 h and poured into ice cold brine (150 mL). Precipitate filtered and washed successively with water and ether to afford the desired product as a white solid (1.5 g, 89%). MS (ESI): mass calcd. for C15H22N6O2Si, 346.2; m/z found, 347.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.50 (d, J=1.4 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.52-8.48 (m, 1H), 4.91 (s, 2H), 4.60-4.45 (m, 2H), 4.25-4.14 (m, 2H), 3.87 (t, J=5.3 Hz, 2H), 1.07-0.92 (m, 2H), 0.01-0.04 (m, 9H).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[O:15][C@@H:14]([C:16]([N:18]([CH:34]2[CH2:36][CH2:35]2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:21]=2)=[O:17])[CH2:13][N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:11]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[CH:34]1([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:21]=2)[C:16]([C@@H:14]2[O:15][C@H:10]([CH2:9][OH:8])[CH2:11][N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:13]2)=[O:17])[CH2:36][CH2:35]1
Reactant: [H][H]
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](COCc3ccccc3)O2)C2CC2)ccc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](CO)O2)C2CC2)ccc1OC
Yield: 107 %

Procedure:
20% Palladium hydroxide-carbon (dry) (22 mg) was added to a solution of tert-butyl(2S,6R)-2-[(benzyloxy)methyl]-6-({cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]amino}carbonyl)morpholin-4-carboxylate (220 mg) in methanol and the mixture was stirred under normal pressure of hydrogen atmosphere at room temperature for 6 hours. After filtration of insoluble materials through Celite, the filtrate was concentrated to give tert-butyl(2R,6S)-2-({cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]amino}carbonyl)-6-(hydroxymethyl)morpholin-4-carboxylate (200 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH2:25]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11])[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 5-methylisatin (8.05 g, 50 mmol) and K2CO3 (8.16 g, 60 mmol) in DMF (100 mL) was added BnBr (6.5 mL, 55 mmol) dropwise over 2 min. After addition, the resulting mixture was heated in an oil bath at 75° C. for 1.5 h. After cooling to rt, the reaction mixture was poured onto ice/cold water (250 mL), rinsed with H2O (50 mL) and stirred for 5 min. The resulting precipitates were collected by suction filtration and air dried to give 1-benzyl-5-methylisatin as dark red solid. MS ESI 252.0 [M+H]+, calcd for [C16H13NO2+H]+ 252.1. 1-Benzyl-5-methylisatin was suspended in DMSO (100 mL) and cooled to 0° C. Hydrazine hydrate (5 mL) was added dropwise over 5 min. After addition, the resulting clear red solution was heated at 120° C. for 2 h then 140° C. for 5 h. After cooling to rt, it was poured into a 1 L Erlenmeyer flask, rinsed with H2O (50 mL) and ice was added until a total volume about 300 mL. 2 M HCl (50 mL) was added and the mixture was extracted with EtOAc (200 mL×2, then 100 mL), and the organic layer was dried (Na2SO4). Removal of solvents followed by drying under high vacuum for 2 days gave the title compound as a dark red solid (12.53 g, quantitative yield over 2 steps, contained some DMSO residue). 1H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 5H), 7.09 (s, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 4.91 (s, 2H), 3.60 (s, 2H), 2.31 (s, 3H); MS ESI 238.0 [M+H]+, calcd for [C16H15NO+H]+ 238.1.
Reaction SMILES: Cl[C:2]1[C:3]2[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][CH2:13][C:4]=2[N:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)O1>>[CH:8]1([C:6]2[N:7]=[C:2]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=3)[C:3]3[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][CH2:13][C:4]=3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=S1(=O)CCCc2nc(C3CCCC3)nc(Cl)c21
Product: COC(=O)Cc1ccc(Cc2nc(C3CCCC3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 45.9 %

Procedure:
Following general procedure H, 4-chloro-2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (0.150 g, 0.52 mmol) was reacted with methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.152 g, 0.52 mmol) to afford the title compound (0.099 g, 46%) as a light yellow oil. MW=414.52. 1H NMR (CDCl3, 500 MHz) δ 7.45 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 4.50 (s, 2H), 3.67 (s, 3H), 3.58 (s, 2H), 3.44-3.40 (m, 2H), 3.27 (quin, J=8.0 Hz, 1H), 3.06 (t, J=6.2 Hz, 2H), 2.48-2.42 (m, 2H), 2.04-1.97 (m, 2H), 1.88-1.73 (m, 4H), 1.70-1.62 (m, 2H); APCI MS m/z 415 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.C[Li].[C:28](=[O:30])=[O:29]>C(OCC)C.O>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2cccc(Oc3ccccc3)c2)cc1
Reactant: O=C=O
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1c(Oc2ccccc2)cccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 11 parts of 1,3-diphenoxybenzene and 40 parts of tetrahydrofuran is added 1 part of methyllithium (as a 1.82 M solution in diethyl ether) while the mixture is cooled in an ice bath. The resulting solution is heated under reflux for 2 hours and then is poured slowly onto 500 parts of dry ice. After the mixture has warmed to room temperature, 100 parts of water are added, and the tetrahydrofuran is evaporated. After the aqueous solution is extracted with 50 parts diethyl ether, it is then acidified with concentrated hydrochloric acid. The white solid which forms is collected to yield 12 parts of 2,6-diphenoxybenzoic acid. The compound is purified by recrystallization from acetonitrile to give 8 parts of pure material, M.P. 164°-165°.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.S(Cl)(Cl)=O.O[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=1.C[O-].[Na+]>CN(C=O)C.O>[C:1]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: OCc1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
A solution of 4-biphenylmethanol (800 g) in DMF (2.4 l) as cooled to 0° C and thionyl chloride (380 ml) was added to the solution for 40 min. The temperature of the reaction mixture was raised to 30±2° C. and stirring was continued for additional one hr. Methyl 4-hydroxyphenylacetate (722 g) was added and stirring was continued for 20 min at this temperature. 28% Sodium methoxide (2.93 kg) was added to the solution for 70 min and stirring was continued for 6 hr while the temperature of the reaction mixture was maintained at 50±2° C. Water (3.21) was added to the reaction mixture for 25 min while the temperature of the reaction mixture was maintained at 50±2° C. which was stirred for additional one hr at same temperature and cooled to room temperature. The precipitate was collected by filtration and washed with methanol (1.6 l) and water (6.41) sequentially to obtain the titled compound (1119 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.CO[CH:13](OC)[CH2:14][NH2:15].[BH4-].[Na+].[C:20](#[N:24])[CH2:21][C:22]#[N:23].CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[NH2:23][C:22]1[N:15]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=2)[CH:14]=[CH:13][C:21]=1[C:20]#[N:24]
Reactant: N#CCC#N
Reactant: COC(CN)OC
Reactant: O=Cc1ccc(F)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1ccn(Cc2ccc(F)c(F)c2)c1N
Temperature: 130 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
A solution of 3,4-difluorobenzaldehyde (38.8 mL, 352 mmol) and 2,2-dimethoxyethanamine (38.3 mL, 352 mmol) in benzene (450 mL) was heated to reflux (130° C.) for 3 h using a Dean Stark trap to separate water. The mixture was concentrated and the residue was dissolved EtOH (450 mL), cooled to 0° C. and sodium borohydride (26.6 g, 704 mmol) was added in portions. Stirring at RT continued for 18 h. The mixture was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated. The residue was dissolved in DCM (1000 mL) and malononitrile (46.5 g, 704 mmol) and 4-methylbenzenesulfonic acid (242 g, 1407 mmol) were added and the mixture was stirred at RT for 18 h. Triethylamine (146 mL, 1056 mmol) was slowly added and the mixture was stirred at 70° C. for 2 h then concentrated. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3/water, brine, dried (Na2SO4), and concentrated. Purification with column chromatography provided 2-amino-1-(3,4-difluorobenzyl)-1H-pyrrole-3-carbonitrile (70 g, 273 mmol, 78% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 3.66-3.83 (br s, 2 H), 4.87-4.95 (s, 2 H), 6.11-6.28 (m, 2 H), 6.75-7.00 (m, 2 H), 7.00-7.35 (m, 1 H); LCMS (m/z) ES+=234 (M+1).
Reaction SMILES: Cl[Si:2](Cl)(Cl)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.O>CO>[SiH3:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Cl[Si](Cl)(Cl)CCc1ccccn1
Solvent: CO
Solvent: O
Product: [SiH3]CCc1ccccn1
Reaction time: 1 h

Procedure:
A solution of 2-(2-silylethyl)pyridine oligosilsesquioxane pillar material was prepared from a methanol solution of 2-(2-trichlorosilylethyl)pyridine (24 grams of 2-(2-trichlorosilylethyl)pyridine in 175 ml of methanol by adding 10.5 ml of water. The mixture was stirred for 1 hour while maintaining the temperature below 30° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:27][C:28]([NH2:30])=[NH:29].C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:27]=[C:28]([NH2:30])[NH2:29])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(N)=NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 132.8 %

Procedure:
The reaction was carried out in a manner similar to Example 84 except for using 2.00 g (10.2 mmol) of 5-chloro-2-indolecarboxylic acid, 1.82 g (11.3 mmol) of carbonyldiimidazole, 5.86 g (61.3 mmol) of guanidine hydrochloride, 6.20 g (61.3 mmol) of triethylamine, 50 ml of tetrahydrofuran and 50 ml of dimethylformamide. Thus 1.85 g (66.2%) of 5-chloro-2-indoloylguanidine hydrochloride was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][CH2:16][CH2:17][CH3:18])=O>N1C=CC=CC=1>[CH2:16]([O:15][C:13]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH2:17][CH3:18]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: CCCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCOc1nc2ccc(C)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A solution of 2-amino-5-methylbenzoic acid (1.0 g, 6.6 mmol) in pyridine (10 ml) was cooled to 0° C. and treated dropwise with propyl chloroformate (3.0 ml, 26 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 4 h, after which time the pyridine was removed in vacuo. The residue was washed with water (25 ml) and dried in vacuo to afford the desired product as an off-white solid (0.96 g, 66%); δH (400 MHz, DMSO-d6) 1.03 (3H, t, J 7, CH2CH3), 1.82 (2H, tq, J, J′ 7, CH2CH3), 2.46 (3H, s, CH3), 4.42 (2H, t, J 7, OCH2), 7.40 (1H, d, J 8, Ph), 7.71 (1H, d, J 8, Ph), 7.89 (1H, s, Ph); m/z (ES+) 219 (MH+).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:4].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl>CN(C=O)C>[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:23][C:22]2[CH:25]=[CH:26][C:27]([Cl:28])=[C:20]([Cl:19])[CH:21]=2)[C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:4]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 57 %

Procedure:
Sodium hydride (488 mg, 60% in mineral oil) was added to a stirred solution of ethyl 3-formylindole-2-carboxylate (2.21 g) in DMF (100 ml) under argon, and reaction stirred at ambient temperature for 25 minutes. 3,4-Dichlorobenzyl chloride (1.71 ml) was then added and the reaction stirred overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (80 ml) and washed with water (2×80 ml), dried (MgSO4) and concentrated in vacuo to give a crude residue which was purified by column chromatography using ethyl acetate:iso-hexane as eluent (gradient 5/95-100/0), to give the product as a yellow solid (2.17 g, 57%); NMR d (CD3SOCD3) 1.25 (t, 3H), 4.40 (q, 2H), 5.80 (s, 2H), 7.00 (m, 1H), 7.30-7.50 (m, 3H), 7.55 (m, 1H), 7.65 (m, 1H), 8.35 (m, 1H), 10.48 (s, 1H); M/z (+) 376.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:24][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[C:2]=1[Cl:1])[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCOC(C(=O)N3CCOCC3)C2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(N2CCOC(C(=O)N3CCOCC3)C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a round bottom flask charged with tert-butyl (2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)carbamate (91 mg, 0.202 mmol) was added dichloromethane (1076 μl) and TFA (269 μl). The reaction mixture was stirred at room temperature 3 h. Excess TFA was removed by concentration in vacuo. The crude residue was free based using a Phenomenex Strata 1 g SCX column. The column was flushed with 3 column volumes methanol and 3 column volumes 3.5 N ammonia/methanol. The ammonia layers were concentrated in vacuo to provide 3-amino-4-chloro-5-(2-(morpholine-4-carbonyl)morpholino)benzonitrile (68 mg, 0.194 mmol, 96%)
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.N[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cc1ccc(N)cc1
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Product: Cc1ccc(N[Si](C)(C)C)cc1
Temperature: 130 °C
Yield: 111.5 %

Procedure:
25 ml of hexamethyldisilazane (0.12 mole) were added in 5 minutes to a mixture of 17.25 g (0.16 mole) of p-toluidine and 0.15 g (0.8 mmole) of saccharin which was heated to 130° C. in an oil bath. By titrating the ammonia evolved during the reaction, it was found that the calculated amount was evolved after refluxing for 2 hours and refluxing was continued for half an hour. The reaction mixture was vacuum distilled to yield 24.0 g (83%) of N-trimethylsilyl-p-toluidine with a boiling point of 98°-102° C. at 12-13 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:3]=1.Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:9][CH:8]=2)[N:3]=1
Reactant: Cc1ccn(-c2ccc(O)cc2)n1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: Cc1ccn(-c2ccc(OCCN3CCCCC3)cc2)n1
Yield: 54 %

Procedure:
The title compound was prepared from 4-(3-methyl-pyrazol-1-yl)-phenol (0.1 g, 0.61 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (0.23 g, 1.25 mmol) using the general procedure C with a yield of 54% (90 mg); 1H NMR (400 MHz, CDCl3) 7.70 (d, J=2 Hz, 1H), 7.52 (d, J=9.2 Hz, 2H), 6.96 (d, J=9.2 Hz, 2H), 6.20 (d, J=2 Hz, 1H), 4.12 (t, J=12, 6 Hz, 2H), 2.78 (t, J=12, 6 Hz, 2H), 2.52 (br, 4H), 2.37 (s, 3H), 1.61-1.47 (m, 6H); LC/MS (ESI): 97%.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([CH:16]2[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[ClH:30].O1CCOCC1>C(Cl)Cl>[ClH:30].[ClH:30].[NH2:22][CH:19]1[CH2:20][CH2:21][CH:16]([N:15]2[C:7]3=[C:8]4[S:14][CH:13]=[CH:12][C:9]4=[N:10][CH:11]=[C:6]3[N:5]=[C:4]2[C@H:2]([OH:1])[CH3:3])[CH2:17][CH2:18]1.[ClH:30]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCC(N)CC1

Procedure:
tert-Butyl (4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)carbamate (0.22 g, 0.53 mmol) was treated with 4.0 M hydrogen chloride in dioxane (0.66 mL, 2.6 mmol) in methylene chloride (3 mL) at room temperature overnight. The mixture was concentrated to give the desired product as HCl salt (0.22 g, 94%). LCMS calculated for C16H21N4OS (M+H)+: m/z=317.1. Found: 317.0.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([CH3:23])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:10]3[C:6](=[CH:7][N:8]([CH3:11])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[C:16]([CH3:23])[CH:15]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: Cn1cc2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cccc3cn(C)nc23)c(C)c1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
7-Bromo-2-methyl-2H-indazole (4; 1.76 g, 8.3 mMol) and tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.25 mMol) were stirred in 15 mL of DME under argon atmosphere for 30 min. 4-Methoxy-2-methylbenzeneboronic acid (1.52 g, 9.2 mMol) was added, immediately followed by a solution of sodium carbonate (3.1 g, 29.1 mMol) in 10 mL water. The mixture was heated at a gentle reflux for 4 hr, and then cooled to rt and diluted with EtOAc (150 mL). The organic phase was washed with brine and dried over magnesium sulfate. Evaporation of the solvent afforded an oil, which was flash chromatographed on SiO2 and eluted with hexane:EtOAc (9:1) to afford 4c (1.9 g; 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:24]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)N1CCCCC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and piperidine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)O)c(OCc2ccccc2)c1
Yield: 53.4 %

Procedure:
A solution of benzyl 2-benzyloxy-4-methylbenzoate acid (25 g) in a mixture of THF and methanol was treated with aqueous 2N NaOH (188 ml) and heated under reflux for 12 hours. The reaction mixture was concentrated to half its volume and was diluted with water, extracted once with EtOAc and the aqueous layer was acidified with HCl to pH4. The solid which precipitated was filtered and dried to give 2-benzyloxy-4-methylbenzoic acid (yield 9.73 g).