Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[CH:13][CH:14]=[C:15]([C:21]([O:23]C)=[O:22])[C:16]([C:17]([O:19]C)=[O:18])=[C:11]2[N:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O>[CH2:1]([N:8]1[C:12]2=[CH:13][CH:14]=[C:15]([C:21]([OH:23])=[O:22])[C:16]([C:17]([OH:19])=[O:18])=[C:11]2[N:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(nc(C)n2Cc2ccccc2)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2c(C(=O)O)c(C(=O)O)ccc2n1Cc1ccccc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
A mixture of dimethyl 1-benzyl-2-methyl-4,5-benzimidazoledicarboxylate (5.50 g, 16.2 mmol), methanol, 10N sodium hydroxide (13 mL, 130 mmol) and Water is stirred for 4 hours at 70° C., cooled, acidified to pH 4 with hydrochloric acid and filtered to afford the title product as an off-white solid (4.94 g, 98.4%), mp 224°-226° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C[C@H](N)C(N[C@H](C(N[C@H](C(N1[C@H](C(O)=O)CCC1)=O)CC(O)=O)=O)CC(N)=O)=O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][O:7][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCBr
Agent: C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: CC(C)(CCCBr)COC1CCCCO1
Temperature: 25 °C
Yield: 108.2 %

Procedure:
5-Bromo-2,2-dimethyl-1-pentanol (77.4 g, 357 mmol) was dissolved in dichloromethane (400 mL), andp-toluenesulfonic acid (6.9 g, 36 mmol) was added. The mixture was stirred under argon, chilled in an ice-bath, then was added 3,4-dihydro-2H-pyran (37.2 g, 428 mmol) and stirred, gradually letting warm to rt overnight. The reaction mixture was then filtered through neutral alumina (100 g); the alumina was rinsed with additional dichloromethane (600 mL). After evaporating to about 500 mL, the organic layer was extracted with sat. NaHCO3 (3′ 200 mL), then dried over MgSO4. The solution was concentrated under reduced pressure to produce the expected product (107.83 g, 97% yield) as a yellow oil. 1H NMR (CDCl3), d (ppm): 4.55 (m, 1H); 3.83 (m, 1H); 3.51 (m, 1H); 3.47 (d, 1 H, J=9.0); 3.38 (t, 2 H, J=6.8); 2.98 (d, 1 H, J=9.0); 1.94-1.75 (m, 2H); 1.75-1.44 (m, 6H); 1.40 (t, 2 H, J=8.5); 0.93-0.87 (m, 6H). 13C NMR (CDCl3), d (ppm): 99.0, 76.2, 61.9, 37.9, 34.6, 34.0, 30.6, 27.9, 25.6, 24.64, 24.56, 19.4. HRMS calcd. for C12H24BrO2 (MH+): 279.0960, found 279.0955.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[N:16]1([C:22]2[CH:27]=[C:26]([C:28](=[O:30])[CH3:29])[CH:25]=[CH:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[C:28]([C:26]1[CH:25]=[CH:24][N:23]=[C:22]([N:16]2[CH2:17][CH2:18][N:19]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:20][CH2:21]2)[CH:27]=1)(=[O:30])[CH3:29]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: CC(=O)c1ccnc(N2CCNCC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccnc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (34 mg, 0.24 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (21 μl, 0.24 mmol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of 1-(2-piperazin-1-yl-4-pyridyl)ethanone (41 mg, 0.2 mmol) and DIPEA (105 μl, 0.6 mmol) in anhydrous DCM (2 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 37 mg of a solid (0.108 mmol, yield 47%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]([CH2:13][C:14](=O)[CH3:15])[CH:11]=O)=[CH:4][CH:3]=1.C(O)(=O)C.C([O-])(=O)C.[NH4+:25].N>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:13]=[C:14]([CH3:15])[N:25]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: COc1nc(Cl)ccc1N(C=O)CC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1nc(Cl)ccc1-n1cnc(C)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A mixture of N-(6-chloro-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (4.71 g), acetic acid (11.1 mL) and ammonium acetate (7.48 g) was stirred at 130° C. for one hour. The reaction solution was left to cool to room temperature. Ice water, ethyl acetate and aqueous ammonia were added and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 2.42 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]1.[CH3:32][O:33][C:34]([NH:36][C@H:37]([C:51](O)=[O:52])[CH:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Si:18]([O:17][CH2:16][C@H:13]1[N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11][C@@H:10]([CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:51](=[O:52])[C@H:37]([CH:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:36][C:34]([O:33][CH3:32])=[O:35])[O:15][CH2:14]1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2ccccc2N)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl (2R,5S)-2-[2-(2-aminophenyl)ethyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate (1 eq.) in DMF (0.15 M) at rt was added N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (1.1 eq.), HATU (1.4 eq.) and 2,6-lutidine (3 eq.). The reaction mixture was stirred at rt for 16 h and diluted with EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by automated SiO2 flash chromatography system using solvent gradient of 10% to 100% EtOAc/Hex to afford the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=2[N+:19]([O-:21])=[O:20])=[CH:5][CH:4]=1.IC.[CH3:24][Si](C)(C)[N-][Si](C)(C)C.[K+]>C1COCC1.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:24][O:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(COc2ccc(CO)cc2[N+](=O)[O-])cc1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1ccc(OCc2ccc(OC)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-({[4-(methyloxy)phenyl]methyl}oxy)-3-nitrophenyl]methanol D117 (2.16 g, 7.47 mmol) in THF (100 mL) was added iodomethane (0.700 mL, 11.20 mmol) followed by the portionwise addition of a 0.5M solution of potassium hexamethyldisilazide (22.40 mL, 11.20 mmol) in toluene. After stirring at rt for 2 hr the mixture was diluted with EtOAc (150 mL) and washed with water (2×50 mL) and brine (2×50 mL). The organic phase was dried (MgSO4) filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-40% EtOAc in isohexane to afford the title compound as a pale orange oil which solidified on standing, 1.57 g, 69.3%.
Reaction SMILES: N1CC[C@H](N(C2CCCCC2)CC(OC)=O)[CH2:2]1.[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:32](=[O:37])[NH:33][CH:34]([CH3:36])[CH3:35])[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:32](=[O:37])[N:33]([CH3:2])[CH:34]([CH3:35])[CH3:36])[CH2:27][CH2:26]1)([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: COC(=O)CN(C1CCCCC1)[C@H]1CCNC1
Reactant: CC(C)NC(=O)N(C1CCCCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)N(C)C(=O)N(C1CCCCC1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared following the procedure described in Step A of Intermediate 128 using 1-BOC-4-[cyclohexyl(isopropylcarbamoyl)amino]piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:35](Cl)=[O:36]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=[C:32]([C:31]([F:30])([F:45])[F:46])[CH:33]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 91, Step 3, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 3,5-bis(trifluoromethyl)benzoyl chloride.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)#[N:30]>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[N:32][CH:33]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1

Procedure:
Compound 54a was prepared from compound 31b and 2-cyanopyridine-5-boronic acid pinacol ester using the methods described in Example 1, Step G. Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H21N7O2: 464.2 [M+H]. found 464.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[C:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:28]4[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]4)=[O:27])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: O=S1(=O)CCNCC1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCS(=O)(=O)CC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), thiomorpholine-1,1-dioxide (44.8 mg, 331 μmol), diisopropylethylamine (145 μl, 828 μmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7.00 ml) is stirred for 4 hours at 70° C. and then for 60 hours at 25° C. under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-(1,1-dioxo-thiomorpholine-4-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (112 mg, 84.7%) as a white solid. mp.: >250° C. MS: m/z=480.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)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>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:3]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][NH:13][C:12]3=[O:16])=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1NCCN1CCNc1ncc(Br)c(-c2cccs2)n1
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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NCCN1CCNc1ncc(-c2ccc(Cl)cc2)c(-c2cccs2)n1
Temperature: 80 °C

Procedure:
1-(2-(5-Bromo-4-(thiophen-2-yl)pyrimidin-2-ylamino)ethyl)imidazolidin-2-one (0.1 g, 0.27 mmol), 4-chlorophenylboronic acid (0.085 g, 0.54 mmol), sodium carbonate (0.27 mL of 2.0 M solution, 0.52 mmol) were added to a flask containing dioxane (1 mL). The flask was flushed with nitrogen and tetrakis(triphenylphosphine)palladium (0.062 g, 0.054 mmol) was added. The reaction was heated to 80° C. overnight. The reaction was cooled down to ambient temperature and diluted with ethyl acetate and water. The organic layer was filtered through a pad of celite and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by column chromatography using a gradient 2 to 10% of methanol in dichloromethane to afford an off-white solid. Yield=0.04 g. MS (M+H)+ 400.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 243 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:8]2.C([BH3-])#N.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:8]2
Reactant: O=C(NN=C1C2CC3CC(C2)CC1C3)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: O
Solvent: C1CCOC1
Product: O=C(NNC1C2CC3CC(C2)CC1C3)OCc1ccccc1
Reaction time: 5 h
Yield: 94.9 %

Procedure:
Under an argon atmosphere, a solution of benzyl 2-(adamantan-2-ylidene)hydrazinecarboxylate (1.60 g, 5.40 mmol) in tetrahydrofuran (54 mL) was added with sodium cyanoborohydride (370 mg, 5.90 mmol) at room temperature, to which a solution of p-toluenesulfonic acid monohydrate (190 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was dropped. The resultant was stirred at the same temperature for 5 hours. The reaction solution was added with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and benzyl 2-(adamantan-2-yl)hydrazinecarboxylate (1.54 g, 94.9%) was obtained as a white crystalline powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:33]1(=[O:39])[NH:37][C:36](=[O:38])[CH:35]=[CH:34]1>>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13]2[CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH:35]3[C:36](=[O:38])[NH:37][C:33](=[O:39])[CH:34]3[C:14]=2[C:15]2[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1)cc(C=Cc1ccccc1OC)n2CCCO[Si](C)(C)C(C)(C)C
Reactant: O=C1C=CC(=O)N1
Product: COc1ccc2c(c1)c1c(n2CCCO[Si](C)(C)C(C)(C)C)CC(c2ccccc2OC)C2C(=O)NC(=O)C12
Yield: 89 %

Procedure:
The reaction of 1-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-5-methoxy-2-[2-(2-methoxyphenyl)ethenyl]-1H-indole (III; Ar=2-methoxyphenyl, R10═CH2CH2CH2OSiMe2t-Bu) (98) prepared as described in example 51 with maleimide using the procedure described in example 68 gave 6-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-9-methoxy-4-(2-methoxyphenyl)-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H, 3aH)-dione (IV; Ar=2-methoxyphenyl; R10═CH2CH2CH2OSiMe2t-Bu) (99) in a 89% yield as a tan powder, which was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:12]=[C:11]([NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:15])[CH:9]=2)[N:4]=1.[CH:16](OCC)(OCC)OCC>>[Cl:1][CH2:2][C:3]1[N:12]2[CH:16]=[N:14][N:13]=[C:11]2[C:10]2[CH:9]=[C:8]([CH3:15])[CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc2nc(CCl)nc(NN)c2c1
Product: Cc1ccc2nc(CCl)n3cnnc3c2c1
Temperature: 100 °C

Procedure:
4. 58.2 g of 2-(chloromethyl)-4-hydrazino-6-methylquinazoline in 870 ml of triethyl orthoformate are heated to reflux temperature while stirring in an oil bath pre-heated to 100° C. and stirred at this temperature for a further 0.5 h. (bath temperature 140°-145° C.). About 40 ml of ethanol are distilled off during the heating. Thereafter, the mixture is concentrated in a vacuum to a volume of about 150 ml. 150 ml of diethyl ether are then added thereto, the mixture is cooled to 0° to 5° C. and the crystals are filtered off. The product is washed with ethanol/diethyl ether 1:2 and with diethyl ether and dried in a vacuum. 55.1 g of crude 5-(chloro-methyl)-9-methyl-1,2,4-triazolo[4,3-c]quinazoline of m.p. 175° C. are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[CH:4][N:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>C(Cl)(Cl)Cl.O>[CH:34]1([NH:37][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[N:10][N:11]4[C:16]=3[CH2:15][CH2:14][CH2:13][N:12]4[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH:5]=[CH:4][N:3]=2)[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: O=C(OCc1ccccc1)N1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCCc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn21
Reaction time: 0.08 h

Procedure:
A solution of the phenylmethyl 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-5,6-dihydropyrazolo[1,5-b]pyridazine-7(4H)-carboxylate (i.e. the product of Step C) (464 mg, 1.0 mmol) and cyclopropylamine (1.3 mL, 18.5 mmol) in chloroform (3 mL) was heated at 120° C. in a sealed tube under microwave irradiation for 1 h and then at 160° C. for 5 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-100% ethyl acetate in hexanes as eluant to give 240 mg of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([SH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Hg](C#N)C#N.[C:21]([O:24][C@@H:25]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:28][S:27][C@@H:26]1Br)(=[O:23])[CH3:22]>>[C:21]([O:24][C@@H:25]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:28][S:27][C@H:26]1[S:13][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:1])[F:15])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: FC(F)(F)c1cc(S)cc(C(F)(F)F)c1
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2cc(C(F)(F)F)cc(C(F)(F)F)c2)SC[C@H]1OC(C)=O
Yield: 35.5 %

Procedure:
If the procedure described in Preparation I is followed starting from 1.6 g (6.5.10-3 mol) of 3,5-bis(trifluoromethyl)benzenethiol, 1.64 g (6.5.10-3 mol) of mercuric cyanide, Hg(CN)2, and 2.54 g (7.5.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.2 g (yield: 35.7%) of the expected product are obtained. M.p.=201° C.
Reaction SMILES: C=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C=O.[O:15]=[O+][O-]>CO.[Pd]>[C:8]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:15]
Reactant: C=C(C(=O)OCC)C(=O)OCC
Reactant: O=[O+][O-]
Agent: [Pd]
Agent: C=O
Solvent: CO
Product: CCOC(=O)C(=O)C(=O)OCC
Yield: 82 %

Procedure:
258 g of diethyl methylenemalonate, prepared by a Knoevenagel condensation of malonic ester and formaldehyde, are dissolved in 1 liter of methanol and reacted with ozone, and subsequently hydrogenated, analogously to the procedure indicated in Example 5. 5 g of 10% Pd-on-C in 200 ml of methanol are initially taken as the hydrogenation catalyst. The consumption of hydrogen is 28.9 standard liters (86% of theory). Working up as in Example 5 and rectification in vacuo gives 214 g of diethyl mesoxalate boiling at 110°-112° C./20, corresponding to a yield of 82% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1
Yield: 72.2 %

Procedure:
A stirred solution of 6-chloroindole (455 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue was recrystallized from ethyl acetate and hexanes to afford a yellow solid (721 mg, 72%).