Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[N:4][C:3]=1Cl.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([O:26][CH3:27])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[N:4][C:3]=1[C:20]1[CH:21]=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([Cl:25])[C:19]=1[Cl:18]
Reactant: Cn1nccc1C(=O)Nc1cnc(Cl)c(N)n1
Reactant: COc1cc(Cl)c(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Cl)c(Cl)c(-c2ncc(NC(=O)c3ccnn3C)nc2N)c1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
N-(6-Amino-5-chloropyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Preparation 2, 0.1 g, 0.396 mmol) was combined with 2,(2,3-dichloro-5-methoxy-phenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 18), (0.156 g, 0.515 mmol), cesium carbonate (0.129 g, 0.396 mmol) and palladium tetrakistriphenylphosphine (0.046 g, 0.04 mmol) and suspended in a mixture of 1,4-dioxane (1 ml) and water (0.5 ml). The reaction was heated at 80° C. for 5 hours. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The residue was partitioned between aqueous sodium carbonate solution (20 ml) and ethyl acetate (20 ml) and the organic layer dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate:heptane 2:3 to 1:1, to afford the product as an off-white solid (72 mg).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:17]#[N:18])=[CH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[BH4-].[Na+].[OH-].[Na+].C(OCC)(=O)C>CO>[CH2:1]([O:3][P:4]([CH:9]([C:17]#[N:18])[CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C#N)=CC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(C#N)CC1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of [1-cyano-2-(tetrahydro-pyran-4-yl)-vinyl]-phosphonic acid diethyl ester (7.45 g, 27.1 mmol) in methanol (200 mL) was added sodium borohydride (5 g, 135 mmol, 5 pellets), portion wise over 1.5 hours. The resulting mixture was stirred an additional 2 hours. The solvent was evaporated in vacuo to yield an oil, to which was added 0.1N NaOH and ethyl acetate. The layers were separated, and the organic layer was dried with MgSO4 and filtered. The solvent was removed to yield an oil which was purified via silica column chromatography (50% EtOAc/heptane) to yield an oil.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15](=[O:20])[C:14]([C:21](N(OC)C)=[O:22])=[N:13]1>C1COCC1>[C:21]([C:14]1[C:15](=[O:20])[C:16]([O:18][CH3:19])=[CH:17][N:12]([C:6]2[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:5]=2[F:4])[N:13]=1)(=[O:22])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cn(-c2ccc(I)cc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(I)cc2F)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 23 %

Procedure:
MeMgBr (1 M solution in THF, 70 mL, 70 mmol) was added dropwise at −78° C. to a solution of 1-(2-fluoro-4-iodophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (9.96 g, 23 mmol) in THF (250 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from MeOH to give the title compound (2.05 g, 23% yield) as pale yellow crystals: mp 196-198° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.67 (3H, s), 3.90 (3H, s), 7.36-7.41 (1H, m), 7.66-7.71 (2H, m), 7.73 (1H, d, J=2.6 Hz). Anal. Calcd for C13H10FIN2O3: C, 40.23; H, 2.60; N, 7.22. Found: 40.25; H, 2.87; N, 7.28.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])OCC[O:44]2)[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].O>C(O)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:44])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: O
Solvent: O=CO
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
(2S,3S,E)-tert-Butyl 3-((S)-3-(4-(but-2-ynyloxy)phenyl)-1-methoxy-1-oxopropan-2-ylcarbamoyl)-11-(2-heptyl-1,3-dioxolan-2-yl)-2-hydroxy-2-(2-methoxyethyl)-undec-4-enoate (1.619 g, 2.136 mmol) was dissolved in formic acid (8.0 mL), and water (420 μL) was added. The reaction mixture was stirred at room temperature for 24 hours, and concentrated. After subsequently repeating twice the operation of dissolution in ethyl acetate and concentration, the residue was purified by diol column chromatography (dichloromethane/ethyl acetate) to obtain the target compound at a yield of 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl-].[Li+].[CH3:29][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:24])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]([OH:19])[CH3:29])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Mg]Br
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(C)O

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of example S.1, Step 1, 0.50 g) and lithium chloride (53 mg, 1.24 mmol, 1.00 equiv.) in THF (15 mL) was added a solution of methyl magnesium bromide (1.78 mL, 1.4 M in THF/toluene, 2.49 mmol, 2.00 equiv.) at −70° C.
Reaction SMILES: F[C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:12][C:13]([F:19])([CH:16]([F:18])[F:17])[CH2:14][OH:15]>>[CH3:11][C:10]1[C:2]([O:15][CH2:14][C:13]([F:19])([F:12])[CH:16]([F:18])[F:17])=[N:3][CH:4]=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: OCC(F)(F)C(F)F
Reactant: Cc1cc(C(=O)O)cnc1F
Product: Cc1cc(C(=O)O)cnc1OCC(F)(F)C(F)F
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (3.7 g, white solid) from 6-fluoro-5-methylnicotinic acid (2.0 g, 12.9 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.4 g, 25.8 mmol) instead of 2,2,2-trifluoroethanol in a similar manner to Step-1 of Amine-1.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].Cl>C(Cl)Cl.O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:7]=1[CH2:15][CH2:14][C:13]2=[O:16]
Reactant: C=CC(=O)Cl
Reactant: Cc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C)c2c1CCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
180 mL CH2Cl2 and 36 g anhydrous AlCl3 (Carlo Erba) were charged in a 3-neck 0.5-L round bottomed flask equipped with magnetic stirring bar, 250-ml dropping funnel, thermometer and reflux condenser. A solution containing 31 ml p-xylene and 21 ml acryloylchloride (Aldrich) in 100 ml CH2Cl2 was placed in the dropping funnel. This solution was added dropwise over 4 hours to the flask, the content of which was kept under stirring at the temperature of 0° C. with a bath of water and ice. Evolution of HCl was observed and the reaction mixture turned dark brick-red. After addition was complete, the mixture was allowed to warm to room temperature and stirring was continued overnight (18 hours). The reaction mixture was poured in a flask containing 250 g ice and 250 ml HCl 37%, the organic phase was separated and the acqueous phase was extracted with Et2O (3 times). All organic fractions were combined and washed with saturated aqueous NaHCO3 and water, dried with Na2SO4, filtered and the solvent was removed in vacuo. 38.25 g of light yellow-orange oil were obtained. This product was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([CH2:8][C:9]([O:11]CC)=[O:10])[C:6]=1[CH3:7].O[Li].O.Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([C:14]([F:16])([F:15])[F:17])=[N:4][N:5]([CH2:8][C:9]([OH:11])=[O:10])[C:6]=1[CH3:7]
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)c(Cl)c1C
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
To a solution of ethyl 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (7.5 g, 27.7 mmol) in THF (100 mL) and water (50 mL) was added LiOH.H2O (2.33 g, 55.4 mmol). The mixture was stirred at 60° C. for 5 hours. After cooling to room temperature, the mixture was acidified with 1 N HCl (80 mL) and extracted with 1:2 IPA/CHCl3 (2×150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the desired compound (6 g, 24.7 mmol, 89%). 1H NMR (400 MHz, DMSO-d6) δ 4.98 (s, 2H), 2.21 (s, 3H); MS: (ES) m/z calculated for C7H6ClF3N2O2 [M+H]+ 243.0, found 243.0.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.N>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[N:7][CH:6]=3)[N:4]=2)=[CH:14][CH:13]=1
Reactant: NC(=NO)c1ccnnc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: N
Product: Fc1ccc(-c2nc(-c3ccnnc3)no2)cc1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 4-fluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.36-7.45 (m, 2H), 8.29-8.40 (m, 3H), 9.45 (dd, J=5.6, 1.2 Hz, 1H), 9.86 (dd, J=2.4, 1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z=243 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][C@@H:3]1[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.C1CCN2C(=NCCC2)CC1.[CH2:32]([C:36]1[N:37]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[S:65](=[O:68])(=[O:67])[NH2:66])=[CH:55][CH:54]=2)[C:38](=[O:51])[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[N:40]=1)[CH2:33][CH2:34][CH3:35]>C1COCC1>[CH2:32]([C:36]1[N:37]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[S:65](=[O:68])(=[O:67])[NH:66][C:5]([C@H:3]3[CH2:4][C:2]3([CH3:8])[CH3:1])=[O:6])=[CH:55][CH:54]=2)[C:38](=[O:51])[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[N:40]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: CC1(C)C[C@@H]1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)[C@H]2CC2(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of (S)-2,2-dimethylcyclopropanecarboxylic acid (194 mg, 1.70 mmol), and carbonyldiimidazole (275 mg, 1.70 mmol) in THF was stirred at 50° C. for 3 hrs. To this was added dropwise a solution of DBU (258 mg, 1.7 mmol) and 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (300 mg, 0.57 mmol) (from Example 16, Step C) in THF. After stirring at 50° C. overnight, the reaction mixture was quenched by addition of 5% citric acid and extracted with EtOAc. The organic layers were combined and washed with water, 5% NaHCO3, and brine, and dried over anhydrous Na2SO4. The crude material obtained after filtration and evaporation of volatiles was flash chromatographed over 60 mL silica gel (gradient elution using 0.5-5.0% MeOH/CH2Cl2) to afford the title compound in 74% yield (263 mg) as a white solid, homogeneous by TLC in 5% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 627 (M+1)+, 649 (M+Na)+ ; mp 93°-95° C.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([C:28]([NH:30][CH3:31])=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[NH2:18][C@@H:19]([C:28]([NH:30][CH3:31])=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22]
Reactant: CNC(=O)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CNC(=O)[C@H](N)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 233.2 %

Procedure:
To a stirring solution of tert-butyl (R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamino)-4-oxobutanoate (226 mg, 0.53 mmol), in DCM (1.05 mL) was added piperidine (263 μL, 2.7 mmol). The reaction mixture was stirred for 1 h at room temperature. The solvent was evaporated to afford 250 mg (100%) of tert-butyl (R)-3-amino-4-(methylamino)-4-oxobutanoate as a mixture with 1-((9H-fluoren-9-yl)methyl)piperidine. The mixture was used without purification in the next reaction. LCMS-ESI (m/z) calculated for C9H18N2O3: 202.1. found 225.1 [M+Na]+, tR=0.50 min. (Method 15).
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]2[CH2:13][CH:12]([NH:14][NH2:15])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.CN(C)/[CH:28]=[CH:29]/[C:30]([C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[OH:39])=O>C(O)C>[C:16]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:13][CH:12]([N:14]3[C:30]([C:32]4[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=4[OH:39])=[CH:29][CH:28]=[N:15]3)[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)/C=C/C(=O)c1cc(F)ccc1O
Reactant: NNC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1ccc(F)cc1-c1ccnn1C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(diphenylmethyl)-3-hydrazinoazetidine dihydrochloride (Preparation 690, 1.25 g, 4.30 mmol) was stirred in ethanol (20 ml) and acetic acid (8 ml) for 30 minutes with ice cooling to give a suspension. To this cold suspension was added (2E)-3-(dimethylamino)-1-(5-fluoro-2-hydroxyphenyl)prop-2-en-1-one (Preparation 221, 900 mg, 4.3 mmol), stirred at 0° C. for 1 hour then allowed to warm up to room temperature over 18 hours. The reaction mixture was evaporated and then partitioned between ethyl acetate (100 ml), water (50 ml) and saturated aqueous sodium hydrogencarbonate solution (30 ml). The organic layer was separated and back-washed with saturated aqueous sodium chloride solution (2×20 ml), dried over sodium sulphate, filtered and evaporated. The solid was triturated with diethyl ether and the off-white solid filtered. The solid was crystallized from ethyl acetate:hexane (1:4) to give the title compound as colourless crystals were. Yield 490 mg 29%.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:23]N1C(=O)CCC1=O>O1CCCC1>[Br:23][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([C:19]([F:21])([F:20])[F:22])=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(C(F)(F)F)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(C(F)(F)F)nnc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To the mixture of 9-pentyl-3-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (50 mg, 0.16 mmol) in tetrahydrofuran (10 mL) was added N-bromosuccinimide (42 mg, 0.24 mmol). The mixture was stirred at 70° C. for 3 hour. The reaction mixture was concentrated and purified by preparative LCMS to yield the desired product. 1HNMR (300 MHz, CD3OD): δ 4.44 (t, J=7.6 Hz, 2H), 1.94 (m, 2H), 1.42 (m, 4H), 0.93 (m, 3H). LCMS calculated for C12H13BrF3N6O (M+H): 393.0. Found: 393.0, 395.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[I:13]Cl>C(O)(=O)C>[Br:1][C:2]1[C:3]([C:9]([F:10])([F:11])[F:12])=[CH:4][C:5]([NH2:8])=[C:6]([I:13])[CH:7]=1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: ClI
Solvent: CC(=O)O
Product: Nc1cc(C(F)(F)F)c(Br)cc1I
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
4-Bromo-3-trifluoromethyl-phenylamine (1.00 g, 4.17 mmol) was dissolved in acetic acid (5 ml). Iodine monochloride (1 M solution in dichloromethane, 5 ml) was added and the mixture was stirred at 60° C. overnight. The reaction solution was poured into a mixture of ice and a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution, an aqueous sodium thiosulfate solution, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give 4-bromo-2-iodo-5-trifluoromethyl-phenylamine (889 mg, 58%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][C:10]=1[F:22])C1C=CC=CC=1>CCO.[Pt](=O)=O>[NH2:21][C:16]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:22])[CH:11]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Nc1ncccc1-c1ccc(OCc2ccccc2)c(F)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ncccc1-c1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A mixture of 3-(4-(benzyloxy)-3-fluorophenyl)pyridin-2-amine (8.5 g), and platinum(IV) oxide (400 mg) in EtOH (200 mL) was stirred at room temperature under hydrogen over weekend. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (3.20 g) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[S:17]([O:8][CH2:7][CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:19])(=[O:18])[CH3:16]
Reactant: CC(C)(C)OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OCCOS(C)(=O)=O
Reaction time: 72 h

Procedure:
Combine 2-t-butoxyethanol (3.37 g, 28.5 mmol), triethylamine (6 mL, 43 mmol), and dichloromethane (150 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (2.9 mL, 37.5 mmol). After 3 days, dilute the reaction mixture with dichloromethane and extract with a saturated solution of sodium bicarbonate and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 2-(t-butoxy)ethyl mesylate: Rf=0.75 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [C:1]([CH:3]=[CH:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH:8]([CH2:23][OH:24])[CH2:7]1)#[N:2].[NH:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36](COCC[Si](C)(C)C)[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH:8]([CH2:23][OH:24])[CH2:7]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=CCN1CCN(C(=O)c2ccc(C#N)cc2F)C(CO)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCC(CN1CCN(C(=O)c2ccc(C#N)cc2F)C(CO)C1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 8 h

Procedure:
4-{[4-[3-cyanoprop-2-en-1-yl]-2-(hydroxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (46 mg, 0.14 mmol, as a mixture of E- and Z-mixtures from Step 2) was combined with 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (29 mg, 0.093 mmol, prepared as described in WO 2007/070514 Example 65) in DMF (0.14 mL) and potassium carbonate (0.0414 g, 0.299 mmol) was added. The reaction mixture was stirred overnight. The mixture was then filtered and the filtrate was diluted with EtOAc. This solution was washed with water (thrice), brine; dried over sodium sulfate, decanted and concentrated. The crude was then stirred in 1:1 DCM:TFA (4 mL) for 1 h and the solvent removed in vacuo. The residue was then stirred with 0.2 mL ethylenediamine in 1.5 mL MeOH for 30 min. Preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) was used to purify product—a mixture of diastereomers (24 mg, 50%). 1H NMR (400 MHz, DMSO-d6, mixture of diastereomers and rotamers): δ 12.12 (br s, 2H), 8.81, 8.80, 8.78, 8.78 (4s, 2H), 8.68, 8.67 (2s, 2H), 8.37, 8.37, 8.36 (3s, 2H), 7.99-7.91 (m, 2H), 7.80-7.72 (m, 2H), 7.63-7.50 (m, 4H), 6.99-6.95 (m, 2H), 5.07-1.84 (m, 28H); LCMS (M+H)+: 514.2.
Reaction SMILES: [C-:1]#[N:2].[CH3:3][C:4]1[CH2:13][NH:12][C:11]2[N:10]=[C:9]([NH2:14])[NH:8][C:7](=[O:15])[C:6]=2[N:5]=1>>[C:1]([C:4]1([CH3:3])[CH2:13][NH:12][C:11]2[N:10]=[C:9]([NH2:14])[NH:8][C:7](=[O:15])[C:6]=2[NH:5]1)#[N:2]
Reactant: [C-]#N
Reactant: CC1=Nc2c(nc(N)[nH]c2=O)NC1
Product: CC1(C#N)CNc2nc(N)[nH]c(=O)c2N1

Procedure:
The first synthesis of 6,6-disubstituted tetrahydropteridines utilized nucleophilic addition of cyanide across the 7,8 double bond of 6-methyl-7,8-dihydropterin, yielding 6-cyano-6-methyltetrahydropterin (Viscontini et al., Helv. Chim. Acta, 54, 811-818 (1971)). After a number of intermediate steps, the nitrile was reduced and the final compound, 6-aminomethyl-6-methyl-5,6,7,8-tetrahydropterin, was obtained. This molecule proved to be less stable than expected, since upon oxidation the resulting quinoid dihydropterin was able to reform the starting 6-methyl-7,8-dihydropterin by loss of the amino methyl group as ammonia and formaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][N:8]=[C:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.S(Cl)([Cl:23])(=O)=O>C(O)(=O)C>[Cl:23][CH2:16][C:15](=[O:17])[C:9](=[N:8][O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:19][CH:18]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NOCc1ccc(C)cc1)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccc(C)cc1)C(=O)CCl
Reaction time: 4 h
Yield: 23.8 %

Procedure:
A mixture of ethyl 2-(4-methylbenzyloxyimino)-3-oxobutyrate (syn isomer, 74.08 g.), sulfuryl chloride (41.70 g.) and acetic acid (75 ml.) was stirred at at 40° to 42° C. for 4 hours. Nitrogen gas was bubbled into the reaction mixture. After adding the mixture into ice water, the mixture was extracted with methylene chloride. The extract was washed with sodium bicarbonate saturated aqueous solution and sodium chloride saturated aqueous solution in turn and dried over magnesium sulfate. After removing the solvent in vacuo, the residue was allowed to stand in a refrigerator overnight. The precipitates were removed by filtration, and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with benzene and ethyl acetate. The eluate was concentrated in vacuo to give ethyl 4-chloro-2-(4-methylbenzyloxyimino)-3-oxobutyrate (syn isomer, 19.9 g.). I.R. νmaxFilm : 3000, 2950, 1740, 1710, 1600, 1440, 1400, 1370, 1340, 1270, 1200, 1000 cm-1.