Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].[Br:19][C:20]1[CH:28]=[N:27][CH:26]=[C:25](F)[C:21]=1[C:22]([OH:24])=[O:23]>C1COCC1>[Br:19][C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[F:11])[C:21]=1[C:22]([OH:24])=[O:23]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1c(F)cncc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1c(Br)cncc1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (54.6 mL, 1.0 M in THF, 54.6 mmol) was added to a solution of 2-fluoro aniline (3.5 mL, 36.4 mmol) in THF (100 mL) at −78° C. The resulting solution was for 1 h at −78° C. 3-Bromo-5-fluoro-isonicotinic acid (1) (4.0 g, 18.2 mmol) was added as a solid, and the reaction solution was stirred for 48 h at room temperature. The reaction solution was concentrated via rotary evaporation, diluted with satd. NaHCO3, and washed with EtOAc. The aqueous solution was acidified with concentrated HCl. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to afford the desired product (4.2 g, 74%) as a yellow solid.
Reaction SMILES: [C:1]([C:6]1(C(OCC)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3]CC)=[O:2].[OH-].[Li+]>C(O)C>[C:1]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Dissolve 2,2-dicarboethoxy-indan (5.67 g, 21.7 mmol) in ethanol (150 mL). Add 1N lithium hydroxide (50 mL) and stir overnight at room temperature Reflux for 1 hour and concentrate the solution in vacuo. Partition between ethyl acetate and 6N hydrochloric acid. Separate the organic phase and wash with brine. Dry (MgSO4) and evaporate the solvent in vacuo to give an off-white solid. Distill (120°-160° C. @0.2-0.5 mmHg) to give 2-carboxy-indan (2.5 g, 71%).
Reaction SMILES: Br[C:2]1[C:3]([N:21]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([NH:26][CH3:27])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[O:19][CH3:20])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:30]1([N:21]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24](=[O:25])[N:26]([CH3:27])[C:2]3[CH:7]=[N:6][C:5]([NH:8][C:9]4[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=4[O:19][CH3:20])=[N:4][C:3]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CNC(=O)C(C)(C)CN(c1nc(Nc2ccc(C(=O)OC)cc2OC)ncc1Br)C1CCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(C)(C)C(=O)N3C)c(OC)c1
Temperature: 100 °C
Yield: 58.9 %

Procedure:
Methyl 4-(5-bromo-4-(cyclopentyl(2,2-dimethyl-3-(methylamino)-3-oxopropyl)amino)pyrimidin-2-ylamino)-3-methoxybenzoate (84 mg, 0.1572 mmol) and Cs2CO3 (74.25 mg, 0.2279 mmol) were dissolved in dioxane (2 mL) and Pd2(dba)3 (4.319 mg, 0.004716 mmol) and Xantphos (7.279 mg, 0.01258 mmol) were added. Heat to 100° C. overnight. The Xantphos and Pd2(dba)3 were replenished and the reaction heated under microwave conditions (120° C. for 30 minutes.) The solvent was removed in vacuo and the crude residue purified by column chromatography (0 to 100% EtOAc/Petrol) to give the title compound as a beige solid (42 mg, 59%); 1H NMR (400.0 MHz, DMSO) d 1.25 (s, 6H), 1.72-1.82 (m, 4H), 1.85-1.95 (m, 2H), 1.98-2.04 (m, 2H), 3.35 (s, 3H), 3.54 (s, 2H), 3.99 (s, 3H), 4.11 (s, 3H), 5.34 (quin, 1H), 7.66 (s, 1H), 7.74 (d, 1H), 7.98 (s, 1H), 8.17 (s, 1H) and 8.64 (d, 1H); MS ES(+) 454.1, ES (−) 452.1.
Reaction SMILES: C(Br)C.[Mg].[C:5]1([C:11]#[CH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=[O:15].[Cl-].[NH4+]>CCOCC>[CH2:19]([O:18][C:13](=[O:17])[C:14]([OH:15])([CH3:16])[C:12]#[C:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:20]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)C(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: CCOC(=O)C(C)(O)C#Cc1ccccc1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A Grignard reagent was prepared under dry nitrogen by the addition over a 1 hour period of a solution comprising 10.9 g (0.10 mole) of ethyl bromide in 15 ml of anhydrous ether to a magnetically stirred suspension of 2.4 g (0.10 g atom) of clean magnesium metal turnings in 70 ml of dry ether. Stirring at 25° C. was continued for an additional hour and then a solution of 10.2 g (0.10 mole) of phenyl acetylene in 15 ml of dry ether was added over 30 minutes. The stirred solution was then heated at reflux for one hour, during which time the acetylenic Grignard reagent separated into a two phase grey-black liquid. After cooling, the two phase liquid was transferred under dry nitrogen to a 200 ml addition funnel followed by flushing with two 15 ml portions of dry ether. The contents of the funnel were rendered homogeneous, by efficient overhead mechanical stirring, and this mixture was added over 35 minutes to a magnetically stirred solution of 11.6 g (0.10 mole) of ethyl pyruvate in 80 ml of dry ether cooled to -20° C. The mixture was stirred at -20° C. for 2 hours and allowed to warm to room temperature overnight. The resulting yellow-orange solution was cautiously treated with 75 ml of saturated ammonium chloride solution and after stirring for 5 minutes, the phases were separated. The aqueous phase was extraced with two 60 ml portions of ether and the combined organic phases were washed with three 75 ml portions of brine and dried over MgSO4. After filtration and concentration at the stripper, a residual reddish-orange oil (19.6 g) was fractionated through a 15 cm Vigreux column to afford, after a small forerun, a single volatile fraction, b.p. 96.0°-105.0° C./0.10 mm. Redistillation of this cut provided 8.9 g (41% yield) of ethyl-2-hydroxy-2-methyl-4-phenylbutynoate, as a colorless, viscous oil, b.p. 98.0°-101.0° C./0.05 mm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.CCN(CC)CC.[CH:17]1([CH:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)[CH2:19][CH2:18]1>CC#N>[Cl:8][C:6]1[CH:7]=[C:2]([N:21]2[CH2:22][CH2:23][CH2:24][CH:20]2[CH:17]2[CH2:19][CH2:18]2)[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: C1CNC(C2CC2)C1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(N2CCCC2C2CC2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (95 mg, 0.576 mmol) in CH3CN (5 mL) was added Et3N (0.25 mL, 1.75 mmol) followed by 2-cyclopropylpyrrolidine (74 mg, 0.50 mmol), and the reaction mixture was stirred for 4 hours at 80° C. The reaction was poured onto water (a precipitate was formed), and filtered. Flash chromatography SiO2 (gradient: EtOAc/hexanes) afforded the title compound (70 mg) as a white solid. LC-MS (ES) m/z=239, 241 [M+H]+.
Reaction SMILES: Br[CH:2]([CH3:5])[C:3]#[N:4].Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[C:16]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=3[O:44][CH2:45][CH3:46])=[N:15]2)=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH2:5][CH2:2][C:3]#[N:4])[CH2:30][CH2:29]3)=[O:27])[C:16]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][C:35]=3[O:44][CH2:45][CH3:46])=[N:15]2)=[CH:12][CH:13]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Reactant: CC(Br)C#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromopropionitrile (10 uL, 0.120 mmol) was added to a mixture of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[piperazin-1-yl]-methanone hydrochloride and diisopropylethylamine (42 uL, 0.240 mmol) in dimethylformamide (1.0 mL). The reaction was stirred at room temperature overnight. Evaporation of the solvent and purification of the crude residue by flash chromatography over silica gel using 1-2% methanol in methylene chloride gave 3-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-propionitrile, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give 3-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-propionitrile hydrochloride as an off-white powder (20 mg, 39% yield). LR-MS (APCI): 644.4 [(M+H)+].
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:19][C:20]3[N:37]=[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[CH2:34][O:35][CH3:36])[N:22]4[N:21]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:36][O:35][CH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]1[N:22]2[N:21]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:11]4[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=4[CH:15]=3)[N:37]=[C:23]2[CH:24]=[CH:25][CH:26]=1
Reactant: COCc1ccccc1-c1cccc2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1ccccc1-c1cccc2nc(Nc3ccc4c(c3)CCNCC4)nn12
Yield: 94.2 %

Procedure:
7-[5-(2-Methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (105.0 mg, 0.210 mmol) was stirred in 3M trifluoroacetic acid in dichloromethane (10 mL) for 30 minutes. The volatiles were evaporated and the residue was dissolved in ethyl acetate and washed with sodium carbonate solution (2×) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Product isolated as a foam (0.079 g, 89%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.64 (d, J=7.7 Hz, 1H), 7.58-7.41 (m, 5H), 7.25-7.21 (m, 1H), 7.16-7.04 (m, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.91-6.87 (m, 1H), 4.35 (br s, 2H), 3.20 (s, 3H), 2.98-2.81 (m, 8H), 2.02 (br s, 1H). MS=400 (MH)+.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5])[OH:2].[CH2:10](O)[CH3:11]>>[CH2:1]([C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O:6][CH2:10][CH3:11])=[O:5])[OH:2]
Reactant: CCO
Reactant: CC(CO)(CO)C(=O)O
Product: CCOC(=O)C(C)(CO)CO

Procedure:
2,2-Bis(methylol)propionic acid (bis-MPA; MW 134.1, 22.1 g, 0.165 mol) was added in ethanol (150 mL) with Amberlyst-15 (6.8 g) and refluxed overnight. The resins were then filtered out and the filtrate was evaporated. Methylene chloride (200 mL) was added to the resulting viscous liquid to filtrate the unreacted reagent and byproduct. After the solution was dried over MgSO4 and evaporated, ethyl 2,2-bis(methylol)propionate (EtMPA) was obtained as a clear and colorless liquid (21.1 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][CH:28]=[C:29]4[C:32]([O:34]C)=[O:33])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][CH:28]=[C:29]4[C:32]([OH:34])=[O:33])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1
Reactant: COC(=O)c1cccc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3cccc(C(=O)O)c3c2)cc1
Temperature: 100 °C
Yield: 81.1 %

Procedure:
A solution of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.122 g, 0.22 mmol) in THF (2.2 mL) was placed in a microwave reaction tube. Methanol (1.1 mL) was added, followed by 1N sodium hydroxide (0.33 mL, 0.33 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 600 seconds. The solution was neutralized and concentrated. Water was added and the mixture was filtered. The resulting solid was dried in a vacuum oven at 45° C. with P2O5 to yield the title compound (0.095 g, 77% as 0.4 tetrahydrofuran) 1H NMR (DMSO-d6): δ 13.3-13.1 (broad s, approximately 1H), 9.05 (s, 1H), 8.14-8.12 (m, 2H), 8.04 (d, J=9 Hz, 1H), 7.82-7.79 (m, 1H), 7.63-7.52 (m, 6H), 6.92 (d, J=9 Hz, 2H), 4.87 (s, 2H), 3.46 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). HRMS C30H23NO4Cl2 m/z 532.1082 (M+H)+Cal; 532.1074 (M+H)+Obs.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([S:21][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: SCc1ccccc1
Reactant: Brc1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnc(SCc2ccccc2)s1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a solution of 2,5-dibromothiazole (2.0 g, 8.23 mmol) in DMF (15 mL) was added K2CO3 (1.16 g, 8.40 mmol) followed by benzyl mercaptan (1.07 g, 8.40 mmol) in DMF (10 mL) over a period of 20 min. The reaction mixture was stirred at RT for over night. After this time, the reaction mixture was diluted with water and extracted in EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (0.2% EtOAc in hexane) to yield 2-(benzylthio)-5-bromothiazole (2.3 g, 97.5% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6, δ): 7.56 (s, 1H); 7.25-7.36 (m, 5H); 4.39 (s, 2H). 1H LCMS Method V: Retention time 2.319 min, [M+1]=286.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:14](=O)[CH3:15])[C:6](=O)[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2].O.[NH2:19][NH2:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:19][NH:20][C:14]=1[CH3:15])=[O:17])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(C(C)=O)C(=O)COC(C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(COC(C)(C)C)n[nH]c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-acetyl-4-tert-butoxy-3-oxo-butyric acid ethyl ester [0.325 g, Reference Example 46] in acetic acid (3 ml) was added hydrazine hydrate (71 μL). The mixture was stirred at ambient temperature for 16 hours and then evaporated to remove the acetic acid. The residue was dissolved in ethyl acetate and the solution was washed with 5% sodium hydrogen carbonate solution, then with water, then dried over magnesium sulfate, and then evaporated to yield 3-tert-butyloxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.258 g) as a yellow oil which was used without further purification. LC-MS (METHOD B): RT=3.22 minutes; 241 (M+H)+.
Reaction SMILES: [CH:1]1[C:6](NN)=[CH:5][CH:4]=[C:3]([N:9]2[CH:13]=NN=C2)[CH:2]=1.[C:14]([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[NH:9]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:1][CH:2]=2)[CH:14]=[CH:13]1
Reactant: O=C([O-])[O-]
Reactant: NNc1ccc(-n2cnnc2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Yield: 44 %

Procedure:
A mixture of 4'-(1,2,4-triazol-4-yl)phenylhydrazine (5.0 g, 28.6 mmol) and 5-(4-tert-butyloxycarbonyl)piperazin-1-yl pentanal dimethylacetal (9.03 g, 28.6 mmol) in 4% sulphuric acid (150 ml) was heated at reflux for 48 h. The solution was cooled in an ice-bath, basified with solid K2CO3 and extracted with butan-1-ol (×3). The solvent was removed under vacuum and azeotroped with hexane (×2). The crude product was purified by chromatography on silica gel eluting with CH2Cl2 /MeOH/NH3 (30:8:1) to give the title-indole (3.9 g, 44%). The 3.5 hydrogen oxalate salt was prepared using 200 mg of free base: mp 90-92° C. (Found: C, 45.97; H, 4.76; N, 13.77. C17H22N6.3.5(C2H2O4) requires C, 46.08; H, 4.76; N, 13.43%); δ (360MHz, D2O) 2.12-2.24 (2H, m, CH2); 2.93 (2H, t, J=7Hz, CH2); 3.46-3.76 (8H, m, 4 of CH2); 7.37 (1H, dd, J=1.9 and 8.7Hz, Ar-H); 7.39 (1H, s, Ar-H); 7.66 (1H, d, J=8.7, Ar-H); 7.82 (1H, d, J=1.9Hz, Ar-H); 9.13 (2H, s, Triazole-H).
Reaction SMILES: N[C@H]([C:5](O)=[O:6])C[SeH].[Li]CCCC.[Si]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)(C(C)(C)C)(C)C.CN(CCN(C)C)C.CN(C=O)C.Cl>C1COCC1>[OH:20][C:21]1[CH:22]=[C:23]([F:28])[C:24]([CH:5]=[O:6])=[C:25]([F:27])[CH:26]=1
Reactant: N[C@@H](C[SeH])C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(F)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=Cc1c(F)cc(O)cc1F
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
Sec-BuLi (1.3M solution in cyclohexane, 53 mL, 69.3 mmol) was added slowly at −78° C. to a solution of intermediate 19, 1-(tert-butyldimethylsilyl)oxy-3,5-difluorobenzene (15.3 g, 62.6 mmol) and TMEDA (10.5 mL, 69.3 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (5.33 mL, 69.3 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1.5 h. Then 10% aqueous HCl was added to attain pH˜4-5 (200 mL), and then the reaction mixture was stirred at RT for 12 h. The aqueous layer was extracted with EtOAc (200 mL). The organic layer was separated. The organic layer was washed with sat. NaHCO3, then H2O was added, HCl was added to attain pH˜3-4, the organic layer was separated, washed with brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (9.7 g, 97%, 61.3 mmol) as a white solid. 1H NMR data (dmso-d6): 11.54 (br.s, 1H, OH), 10.00 (s, 1H, CHO), 6.50-6.57 (m, 2H, H—Ar).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:28][C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[N:17][CH:18]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][S:25][CH2:24][CH2:23]4)[CH:20]=3)[N:12]=[C:11]([CH3:37])[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O.OS(C(F)(F)F)(=O)=O>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([NH:28][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:37])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][S:25][CH2:24][CH2:23]3)=[CH:18][N:17]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCSCC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CN3CCSCC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 54.8 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(thiomorpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (86 mg, 0.129 mmol) in 2 mL of TFA was treated with 2 drops of triflic acid. The brown solution was heated in an oil bath at 80° C. for 5 h. The volatiles were removed on and the dark residue was basified with 1 N NaOH and extracted with EtOAc twice followed by DCM once. The combined organic extracts were concentrated and purified on a Redi-Sep pre-packed silica gel column (12 g) eluting with a gradient of 2-6% MeOH in DCM to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(thiomorpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (30 mg, 55% yield) as an orange crystalline solid. 1H NMR (400 MHz, d6-DMSO) δ 11.75 (1H, s); 8.68 (1H, d, J=2.4Hz); 8.54 (1H, d, J=2.7 Hz); 8.18 (1H, d, J=2.5 Hz); 8.16 (1H, d J=2.9 Hz); 7.87 (1H, br. s); 7.73 (1H, br. s); 6.82 (1H, d, J=9.0 Hz); 3.84 (3H, s); 3.46 (2H, s); 2.67-2.60 (8H, m); 2.44 (3H, s). m/z (ESI, +ve ion) 425 (M+H)+.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH3:26][C:24]1[CH:23]=[C:22]([CH3:27])[N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 60° and 70° C., to a solution of 2-amino-4,6-dimethylpyridine (2.4 g) and triethylamine (4.1 g) in dioxane (100 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 25 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 5 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue is dissolved in methylene chloride (400 cc). The solution obtained is washed with distilled water (100 cc), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 3 times with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (6.3 g) is thereby obtained, which is dissolved in boiling acetonitrile (140 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 20° C. for 1 hour. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (20 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(4,6-dimethyl-2-pyridyl) 3-(3-pyridyl)-1H,3H-pyrrolo-[1,2-c]thiazole-7-carboxamide (3.9 g) in the form of white crystals, m.p. 171° C., is thereby obtained.
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]2[CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:15]=2[Cl:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCC2)N1Cc1cccc(Cl)c1Cl

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 68, and 2,3-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a pale yellow oil.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10]>>[CH2:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: COP(OC)OC
Product: CCOC(=O)P(=O)(OC)OC

Procedure:
From 10,0 ml (85 mmole) of trimethylphosphite and 10.0 ml (105 mmole) of ethyl chloroformate (100° C., 1,5 hours). Yield 12,5 g (80%). Bp15 122° C.