Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 60 °C

Procedure:
3-Hydroxy-4-nitro-benzoic acid (10 g) was dissolved in MeOH (500 ml). 96% H2SO4 (2 ml) was added, and the mixture was heated to 60° C. for 18 hours. The reaction mixture was concentrated to approx. 200 ml, diluted with EtOAc (200 ml) and washed with an aqueous saturated solution of NaHCO3 (2×20 ml). The organic layer was dried over Na2SO4 and the solvent was removed by evaporation to yield 10.5 g of the desired intermediate.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11]([CH:13](P(OC)(OC)=O)[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:12].[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[N+:42]([O-:44])=[O:43])[CH:37]=O)([O-:33])=[O:32]>O1CCCC1>[CH3:9][O:10][C:11](=[O:12])[C:13]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[CH:37][C:36]1[CH:39]=[CH:40][C:41]([N+:42]([O-:44])=[O:43])=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,1,3,3-Tetramethylguanidine (41.2 mL, 329 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)-alpha-phophonoglycine trimethyl ester (114.1 g, 344 mmol) in tetrahydrofuran (800 mL). The mixture was stirred at room temperature for 15 min and cooled to −78° C. A solution 3,4-dinitro-benzaldehyde (61.4 g, 313 mmol) in tetrahydrofuran (200 mL) was slowly added via cannula. The resulting mixture was stirred at −78° C. for 2 h and then allowed to warm to room temperature overnight. Solvents were removed in vacuo, and the yellow residue was dissolved in 4.5 L of ethyl acetate. The solution was washed with 1.5 L of 1N sulfuric acid, water twice, brine and dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was crystallized from ethyl acetate (20 g crude product/100 mL of ethyl acetate). The yellow crystals were collected and further purified by chromatography on silica gel using methylene chloride as eluent. The title compound was obtained a s yellow crystals (77%). 1H-NMR (CDCl3, 500 MHz) δ 7.85 (d, J=1.5 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.62 (dd, J=8.5, 1.5 Hz, 1H), 7.35–7.34 (m, 3H), 7.34 (br s, 2H), 7.23 (s, 1H), 6.95 (br s, 1H), 5.07 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: N12CCCN=C1CCC[CH2:3][CH2:2]2.[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][N:23]=1.ICC>O>[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[N:32]([CH2:2][CH3:3])[N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:26])([CH3:27])[CH3:25])=[N:22][N:23]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n2)CC1
Solvent: CCI
Solvent: O
Product: CCn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 35 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (76 mL, 511.14 mmol) was added to a suspension of tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (150 g, 319.46 mmol) in 2-methylTHF (1.2 L). Iodoethane (46 mL, 575.03 mmol) was added and the mixture was stirred for 16 hours at 35° C. Further iodoethane (46 mL, 575.03 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (76 mL, 511.14 mmol) were added and stirring was continued for 24 hours at 35° C. The mixture was poured into water and the insoluble material was isolated by filtration, washed with water and MTBE and dried in vacuo to afford tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (116 g, 73.0%) as a yellow solid. The filtrate was extracted with DCM and the organic solution was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution (30% MTBE/heptane to 100% MTBE). A second crop of the desired product (12 g, 24.12 mmol, 7.55%), was thus isolated as a yellow solid which was later combined with the first crop: 1H NMR Spectrum: (DMSO-d6) 1.41 (9H, s), 1.44 (9H, s), 1.48 (3H, t), 1.52-1.69 (2H, m), 1.87-2.04 (2H, m), 2.79-3.03 (3H, m), 3.86-4.03 (2H, m), 4.59 (2H, q), 7.89 (2H, s), 8.85 (1H, s); Mass Spectrum [M+H]+=498. THF may also be a suitable solvent for the above reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19](O)=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][CH2:19][OH:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a mechanically stirred suspension of (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid 1a (5.0 g, 17.9 mmol) in THF (50 ml) at 0° C. under nitrogen atmosphere was added dropwise a 1.0 M solution of borane-tetrahydrofuran complex (56 ml, 56 mmol). The mixture was slowly warmed to ambient temperature and stirred for 2 h (nearly homogeneous at this point, slightly hazy). The reaction was quenched with 1.0 N HCl at 0° C., and stirred at ambient temperature for 0.5 h. The solution was concentrated in vacuo in order to remove the volatiles. The resulting solution was basified at 0° C. with 10% NaOH and extracted with dichloromethane (2×250 ml). The organic layers were combined, dried (Na2SO4), and concentrated to afford 4.4 g (93%) of product as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.80 (broad s, 1H), 2.29 (s, 3H), 2.37 (s, 3H), 3.21 (t, J=6.2 Hz, 2H), 4.00 (t, J=6.2 Hz, 2H), 6.82 (dd, J=1.5, 8.8 Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 7.29 (d, J=9.1 Hz, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.84 (s, 1H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][C:14](OCC)=[O:15]>>[CH2:19]([C:12]1[CH:13]=[C:14]([OH:15])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Product: N#Cc1ccnc(-n2nc(Cc3ccccc3)cc2O)c1
Yield: 53 %

Procedure:
The title compound was prepared in 53% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-oxo-4-phenylbutanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H12N4O, 277; Found, 277.
Reaction SMILES: [Na].[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][NH2:7])[CH3:3].Cl.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[CH:17][N:18]=[N:19]2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([S:29]([NH:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:2][CH3:3])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[CH:17][N:18]=[N:19]2)=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Reactant: CCN(CC)CCN
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Temperature: 5 °C

Procedure:
A mixture of anhydrous sodium carbonte (3.08 g) and N,N-diethylethylenediamine (0.43 ml) in chloroform (30 ml) was vigorously stirred at 5° C. and treated with 4-(7-Chloro-4-cinnolinylamino)benzenesulphonyl chloride hydrochloride (1.0 g). The mixture was stirred at room temperature for 11/2 hours and then filtered. The filtrate was evaporated to give a residue that crystallised from ethanol to give the title compound (0.456 g), m.p. 175°-76° C.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=3)=[N:14]2)=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(Br)n1
Yield: 62.7 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-bromo-1,3-thiazole-4-carboxylic acid (0.957 g, 4.60 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1 g, 3.84 mmol). Yield 62.7%. 1H-NMR (400 MHz; CDCl3): δ 1.32 (d, 3H), 4.36 (dd, 1H), 4.46 (dd, 1H), 4.58-4.63 (m, 1H), 6.63 (d, 1H), 7.51 (d, 1H), 7.65 (d, 1H), 7.70 (d, 1H), 7.76 (dd, 1H), 7.93 (d, 1H), 7.40 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([Li])CCC.CCCCCC.[CH:26](N1CCOCC1)=[O:27]>CCOCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]([CH:26]=[O:27])=[CH:13][N:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cnc(-c2ccc([N+](=O)[O-])cc2)s1
Reaction time: 0.5 h

Procedure:
As depicted in Scheme 25 below, 2-(4-nitrophenyl)thiazole (19.9 mmol) dissolved in ether (20 ml) is added dropwise over 1 hour to a stirred and cooled (−78° C.) solution of butyl lithium (1.5 M) in n-hexane (20 ml, 29.9 mmol), diluted with ether (50 ml). The mixture is stirred at −78° C. for 30 minutes and then a solution of N-formylmorpholine (29.9 mmol) in ether (30 ml) is added dropwise over a time period of 15 minutes. After 30 minutes at −78° C., the mixture is washed with saturated aqueous NaHCO3 (30 ml) and extracted with ether (2×20 ml). The organic phase is dried over Na2SO4 and the solvent is removed under reduced pressure to give the crude 2-(4-Nitro-phenyl)-thiazole-5-carbaldehyde.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.C(N(CC)CC)C.Cl.[C:23]1([C:29]2([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:37]3[C@@H:33]([CH2:34][NH:35][CH2:36]3)[C@@:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH3:46])([OH:38])[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:47]1([C:29]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:37]3[C@@H:33]([CH2:34][N:35]([C:11](=[O:12])[C:10](=[O:14])[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)[CH2:36]3)[C@@:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH3:46])([OH:38])[CH2:31][CH2:30]2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)C(=O)c3c[nH]c4ccccc34)C[C@H]21
Yield: 97.3 %

Procedure:
A solution of 0.43 g of 2-(3-indolyl)-2-oxoacetyl chloride in 20 cm3 of dry dichloromethane and then a solution of 0.6 cm3 of triethylamine in 5 cm3 of dry dichloromethane are added in succession to a suspension of 0.96 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride in 25 cm3 of dry dichloromethane at room temperature, while stirring. The reaction mixture is stirred at this temperature for 24 hours, subsequently diluted with 200 cm3 of dichloromethane, washed with 100 cm3 of an aqueous 1N solution of sodium hydroxide and with 50 cm3 of an aqueous saturated solution of sodium chloride, and is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.5 cm, height 1 cm) by eluting under a pressure of 0.4 bar of nitrogen with a mixture of 1,2-dichloroethane and methanol (70/30 by volume) and collecting fractions of 15 cm3. Fractions 2 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.15 g of (3aS,4S,7aS)-7,7-diphenyl-2-[2-oxo-2-(3-indolyl)acetyl]-4-(2-methoxyphenyl)perhydroisoindol-4-ol are obtained in the form of an orange foam.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:19][S:20](O)(=[O:22])=[O:21].C(Cl)(Cl)Cl.[Cl-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:13]1[CH:14]=[CH:15][C:16]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCCCCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 24.6 grams (0.1 mole) of n-dodecylbenzene in 150 ml of carbon tetrachloride was added with stirring 34.8 grams (0.3 mole) of chlorosulfonic acid over a 1-hour period. The reaction was exothermic with the temperature rising to 27° C. Stirring was continued for 4 hours after which the reaction mixture was carefully poured onto 1 liter of cracked ice with vigorous stirring. Chloroform (200 ml) was added and the aqueous layer was saturated with sodium chloride. The chloroform layer was separated, washed two times with 500 ml of saturated aqueous sodium chloride solution, dried over Molecular Sieves 4A and filtered. The solvent was removed in vacuo, and the resulting residue was recrystallized from 100 ml of hexane. The dried product weighed 22.6 grams and melted at 33°-35° C.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:15]1[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([F:12])[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=1
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Reaction time: 3 h
Yield: 122.4 %

Procedure:
Dibromoisocyanuric acid (1.49 g) was added at room temperature to a DMF (50 mL) solution of 2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (2.02 g), and the mixture was stirred at the same temperature as above for 3 hours in a nitrogen atmosphere. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.99 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][OH:13])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(O)COCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Reaction time: 3 h
Yield: 102.9 %

Procedure:
To a mixture of 1-O-benzyl-glycerol (27 mL, 0.16 mol) and t-butyldimethylsilyl chloride (25 g, 0.17 mol) in dry CH2Cl2 (250 mL) under N2 was added DMAP (0.8 g, 6.6 mmol) followed by the addition of TEA (23 mL, 0.17 mol). After 3 hours, the mixture was washed with H2O (2×100 mL), dried (MgSO4) and concentrated to give 1-O-benzyl-3-O-t-butyldimethylsilyl-rac-glycerol (40) (48.8 g, 100%) as a yellow oil.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:8]#[CH:9])=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.[I:22]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>ClCCl>[S:1]1[C:5]([CH2:6][CH:7]([O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])/[CH:8]=[CH:9]/[I:22])=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: O=C1CCC(=O)N1I
Reactant: C#CC(Cc1cc2ccccc2s1)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(/C=C/I)Cc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Cp2ZrHCl (1.719 g, 6.67 mmol) was added to a solution of 9-5 (1.372 g, 4.34 mmol) in dichloromethane (30 mL). The reaction was stirred for 30 min. at room temperature and N-iodosuccinimide (1.997 g, 8.88 mmol) was added. After 1 h, the reaction was poured into 100 mL of saturated NaHCO3 solution. The resulting mixture was extracted with dichloromethane (3×75 mL) and the combined organic extracts were dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (2% ethyl acetate/hexanes) gave 9-6 (1.7484 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH:8]([CH3:13])[N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[CH3:20]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH2:9][CH:8]([CH3:13])[N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: CC(=O)N(C)C
Reactant: CC1CC(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC1CC(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.28 g (0.001 mole) of (rac)-2-chloro-9-cyclopentyl-8-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 2 mL of N,N-dimethylacetamide and 0.093 mL (0.0015 mole) of iodomethane at 0 degrees was added 0.06 g (0.0015 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 10 mL of water was added. The precipitate collected by filtration to give 0.278 g of (rac)-2-chloro-9-cyclopentyl-5,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-3) as an yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32][N:31]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:36]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:37])=[CH:32][N:31]=1
Reactant: COc1c(OCc2ccc(S(C)(=O)=O)cc2)ccc2c1N=C(N)N1CCN=C21
Reactant: Nc1ncc(C(=O)O)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCc2ccc(S(C)(=O)=O)cc2)ccc2c1N=C(NC(=O)c1cnc(N)nc1)N1CCN=C21
Reaction time: 8 h
Yield: 12.1 %

Procedure:
7-Methoxy-8-{[4-(methylsulfonyl)benzyl]oxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 1, 76 mg, 0.19 mmol) was dissolved in DMF (5 mL), and 2-aminopyrimidine-5-carboxylic acid (40 mg, 0.29 mmol) was added. PyBOP (152 mg, 0.29 mmol) and diisopropylethylamine (0.15 mL, 0.85 mmol) were subsequently added. The mixture was stirred at it overnight, during which a tan solid precipitated. The DMF was removed under reduced pressure and the residue purified via silica gel chromatography (0-3% MeOH/CH2Cl2+0.1% Et3N). The solvent was evaporated under reduced pressure, the residue triturated in water (5 mL), collected by vacuum filtration, then washed with acetone. High vacuum drying gave the title compound (12 mg, 12%): HPLC MS RT=2.06 min, MH+=522.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.22 (3H, s), 4.00 (3H, s), 4.19-4.25 (2H, m), 4.48-4.55 (2H, m), 5.53 (2H, s), 7.53 (1H, d), 7.77 (2H, d), 7.97-8.03 (3H, m), 9.06 (2H, s).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25](Br)[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:33][Sn](C)(C)C>CN(C)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>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25]([CH3:33])[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(Br)c3C[C@H]2O)C1
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(C)c3C[C@H]2O)C1
Temperature: 110 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
According to Scheme 13: A mixture of 3-[5-acetyl-1-((1R,2R)-4-bromo-6-fluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11d) (0.05 g, 0.10 mmol), tetramethyltin (101 mg, 0.566 mmol) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) in N,N-dimethylformamide (2 ml) was stirred at 110° C. for 18 h. The mixture was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 23 mg of 3-[5-acetyl-1-((1R,2R)-6-fluoro-2-hydroxy-4-methyl-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (19a).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[CH2:20]([C:21]1[O:18][C:5]2[C:6]([C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:19]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(Cc1ccccc1F)c1cc(F)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(F)cc2c(=O)c1-c1ccccc1F
Temperature: 25 °C
Yield: 63.1 %

Procedure:
Intermediate 66 (1.1 g, 4.43 mmoles) was taken in a RB flask and to this triethylamine (10 ml) and propionic anhydride (1.80 g, 13.86 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.800 g, 63% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 7.82(dd, J=9.0,4.4Hz, 1H), 7.75(m,2H), 7.50(m,1H), 7.37-7.28(m, 3H), 2.56(m,2H), 1.19(t, J=7.6Hz, 3H).