Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([F:31])[CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([F:31])[CH:20]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1F
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1F
Yield: 67 %

Procedure:
Following General Procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100 g, 0.33 mmol) was reacted with ethyl 2-(4-amino-2-fluorophenyl)acetate (0.098 g, 0.50 mmol) to afford the title compound (0.094 g, 94%). MW=424.90. 1H NMR (CD3OD, 300 MHz) δ 7.79-7.75 (m, 1H), 7.66-7.60 (m, 1H), 7.45-7.36 (m, 2H), 7.30 (t, J=8.4 Hz, 1H), 7.20 (s, 1H), 7.11-7.05 (m, 1H), 7.04-6.97 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 3.02 (t, J=7.6 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.30-2.13 (m, 2H), 1.26 (t, J=7.6 Hz, 3H); APCI MS m/z 425 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH3:16])[C:12](Br)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:26])([F:25])C([O-])=O.[Na+]>[Cu]I.CN1CCCC1=O>[CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH3:16])[C:12]([C:21]([F:26])([F:25])[F:20])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: Cc1c(Br)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1c(C(F)(F)F)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 160 °C

Procedure:
A mixture of 1.50 g (4.66 mmol) of 3-benzyloxy-6-bromo-2-nitrotoluene, 6.33 g (46.6 mmol) of sodium trifluoroacetate, 4.43 g (23.3 mmol) of copper (I) iodide and 80 ml of N-methylpyrrolidone was heated at 160° C. for 7 hours while stirring. Next, the solvent was distilled off under reduced pressure and ethyl acetate was added to the resulting residue. Insoluble matters were then filtered off. The filtrate was washed twice with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was isolated and purified by silica gel column chromatography to give 0.70 (48.3%) of 3-benzyloxy-6-trifluoromethyl-2-nitrotoluene.
Reaction SMILES: O=O.[CH2:3]([N:10]1[CH2:15][C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:13]([C:23]([OH:25])=[O:24])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[H][H]>[OH-].[Na+].CC(OC)(C)C.CO>[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([C:23]([OH:25])=[O:24])[CH:14]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)CC1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Yield: 72.8 %

Procedure:
A 185-mL stainless steel autoclave was charged under argon in a glove box (O2 content<2 ppm) with the hydrochloride salt of 1-benzyl-5-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid (7.00 g, 21.36 mmol), [Ru(OAc)2((R)-(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(di-2-furylphosphine)] (81.30 mg, 0.11 mol), [Ru(OAc)2((S)-(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(di-2-furylphosphine)] (81.30 mg, 0.11 mol), triethylamine (3.00 mL, 21.42 mmol) and methanol (120 mL). The hydrogenation was run for 20 h at 30° C. under 40 bar of hydrogen. After the pressure was released, the white suspension was evaporated to dryness to yield 9.58 g of the crude title compound. The crude product was dissolved in 1 M NaOH (45 mL). TBME (50 mL) was added, the aqueous layer was separated and diluted with water (250 mL). Under stirring 2 M HCl (20.5 mL) was added (pH value=6.0). The formed precipitate was filtered off and washed with water (50 mL). The filter cake was dissolved in methanol (100 mL) and the colorless solution evaporated to dryness to yield 5.13 g (70%) of the title compound. MS (m/e): 330.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)[CH2:54][CH2:53][O:52]1.C(O)CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:54][CH2:53][OH:52])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)OCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (US20100152190A1, 197 mg, 0.320 mmol,) in methylene chloride (8 mL) was added triethylamine (97.0 mg, 0.14 mL, 0.959 mmol) followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (Aldrich, 114 mg, 0.447 mmol). The mixture was stirred at room temperature for 10 min before ethane-1,2-diol (Aldrich, 122 mg, 0.11 mL, 1.97 mmol) was added. This reaction mixture was stirred at room temperature overnight. It was then diluted with methylene chloride and washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (eluting with hexane/ethyl acetate, 80/20 to 10/90) to give chiral 2-hydroxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (112.2 mg, 53% yield). MS (ES+) m/z calcd. for C33H34Cl2F2N3O5 [(M+H)+]: 660. found: 660.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2.C(N(C(C)C)CC)(C)C.CC([OH:51])C>C(Cl)Cl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:51])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[NH:32][CH:33]=[N:34]3)[CH2:6]1
Reactant: CC(C)O
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@]1(C(=O)O)CN(c2ncnc3nc[nH]c23)C[C@@H]1CCCB(O)O
Temperature: 80 °C
Yield: 20 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 2-propanol (5 mL) was treated with 6-chloropurine (92 mg, 0.6 mmol) and diisopropylethylamine (0.174 mL, 1.0 mmol), heated to 80° C. for 18 h, then diluted with methylene chloride (20 mL). The mixture was filtered through Celite® and the filtrate concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(7H-purin-6-yl)pyrrolidine-3-carboxylic acid (41 mg, 20%) as a pale amber solid. NMR (D2O) δ 8.20-8.45 (m, 2 H), 4.20-4.60 (m, 2 H), 3.50-4.00 (m, 2 H), 2.60-2.80 (m, 2 H), 1.65 (m, 1 H), 1.20-1.55 (m, 3 H), 0.65-0.75 (m, 2 H). MS (m+1): 335.2; MS (m−H2O+1): 317.1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>C(COC)OC>[Cl:16][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:11][C:2]3[N:3]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:1]=3)=[CH:8][CH:7]=1
Reactant: CC(C)Oc1cc(N)nc2cc(Cl)ccc12
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c(cc(OC(C)C)c3ccc(Cl)cc32)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.9 g of 2-amino-7-chloro-4-isopropoxyquinoline were dissolved in 20 ml of dimethoxyethane and 1.9 g of ethyl bromopyruvate were added thereto followed by 800 mg of triethylamine. The mixture obtained was stirred at room temperature for 4 hours and then the solvent was evaporated under vacuum. The residue was dissolved in 100 ml of chloroform and the solution was dried over MgSO4 and was evaporated to dryness under vacuum. The residue was dissolved in 25 ml of ethanol and the solution was refluxed for 3 hours and then the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel-chloroform/methanol eluant) and then was crystallized from diethyl ether to obtain pale cream needles of ethyl 8-chloro-5-isopropoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 187°-189° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.[CH2:23]([N:25]([CH2:28]C)[CH2:26]C)C>C1COCC1.ClCCl>[CH3:23][N:25]([CH:28]=[N:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[CH3:26]
Reactant: Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C=Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 5-amino-3-(4-quinolylmethylen)-2-oxindole (287 mg, 1 mmol) and triethylamine (121 mg, 1.2 mmol) in THF (20 ml) was added portionwise at, 0° C. chlorodimethyl-formimminium chloride (154 mg, 1.2 mmol) and the stirring was continued at room temperature for 1 h. Then the reaction mixture was diluted with dichloromethane, the organic layer washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel (eluant ethyl acetate/methanol 1:1) to give pure title compound in 60% yield (205 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][CH:17]=2)[N:12]([C@:28](O[SiH3])([CH3:46])[C:29](C2C=CC=CC=2)(C2C=CC=CC=2)C(C)(C)C)[C:11]1=[O:49].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:68]1CCCC1>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:16][CH:17]=2)[N:12]([C@@H:28]([CH3:46])[CH2:29][OH:68])[C:11]1=[O:49]
Reactant: COc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@@](C)(O[SiH3])C(c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)c(F)c1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@@H](C)CO)C2=O)c(F)c1
Reaction time: 4 h

Procedure:
(S)-3-(2-Fluoro-4-methoxy-phenyl)-7-(4-fluoro-phenylamino)-1-(2-tert-butyl-diphenyl-silanyloxy-1-methyl-ethyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.33 g, 0.46 mmol) was dissolved in anhydrous tetrahydrofuran (3.5 mL) and treated with tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.90 mL, 1.90 mmol) (Aldrich). The reaction was stirred in a water bath that was maintained in the 25–35° C. range. The reaction was complete after 4 hours and was concentrated. The residue was redissolved in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (Biotage 40S, 75:25 ethyl acetate-hexanes) followed by crystallization from ethyl acetate-hexanes gave (S)-(+)-3-(2-fluoro-4-methoxy-phenyl)-7-(4-fluoro-phenylamino)-1-(2-hydroxy-1-methyl-ethyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 0.18 g, 83.5%). Melting Point: 173–177° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37](O)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=2)[C:19]([CH3:40])=[C:18]3[CH3:41])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37](=[O:38])[NH:46][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:29][CH:30]=2)[C:19]([CH3:40])=[C:18]3[CH3:41])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)NS(C)(=O)=O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of (S)-4′-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (30 mg, 0.055 mmol), methanesulfonamide (15 mg, 0.16 mmol), EDAC (25 mg, 0.13 mmol) and DMAP (26 mg, 0.21 mmol) in DMF (3 mL) was stirred at rt for 15 h. The solvent was removed and the residue was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to obtain the title compound. ESI-MS (m/z): 622 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1>[CH3:8][O:9][C:10](=[O:20])[CH:11]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
2.5M nButyllithium in hexanes (37.5 ml, 0.094 mol) was added, in a dropwise fashion, to a solution of diisopropylamine (14.45 ml, 0.103 mol) in tetrahydrofuran (300 ml) at 0° C. The solution was stirred at 0° C. for 20 minutes. The mixture was then cooled to −70° C. and a solution of (3,4-dichloro-phenyl)-acetic acid methyl ester (20.54 g, 0.094 mol) in tetrahydrofuran (50 ml) was added dropwise via cannula. The reaction mixture was stirred at −70° C. for 30 minutes. After this time, tert-butyl bromoacetate (45.42 ml, 0.281 mol) was added in a dropwise fashion. The cooling bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was quenched with a saturated solution of NH4Cl (100 ml). THF was partially removed in vacuo and the mixture was extracted with EtOAc (3×200 ml). The combined organic extrats were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography using as eluent petrol: ether (9:1) to give the title compound in 92% yield.). 1H NMR (400 MHz, DMSO-d6) δ 1.34 (9H, s), 2.65 (1H, dd), 2.98 (1H, dd), 3.60 (3H, s), 4.08 (1H, m), 7.31 (1H, m), 7.58–7.62 (2H, m); MS (ES+): m/e=333.2 (5%); MS (ES−): m/e=331.2 (100%), 333.2 (65%), 335.2 (10%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH2:12][NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:5]2[N:4]=1.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:31])C=1>>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH2:12][NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:5]2[N:4]=1)=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2ccc(CNc3ccccc3)n2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(CNc3ccccc3)n2n1
Yield: 27.9 %

Procedure:
(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-phenyl-amine (0.280 g, 1.04 mmol) was dissolved in Methylene chloride (5 mL, 80 mmol) and the solution was treated with m-Chloroperbenzoic acid (0.313 g, 1.40 mmol) at room temperature. The reaction was allowed to stir until HPLC showed consumption of starting materials. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was purified by Isco flash column chromatography (hexanes/ethyl acetate eluent) and combined fractions were reduced and dried under vacuum to afford 83 mg of (2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-phenyl-amine. (M+H)=287.0. 1H NMR (400 MHz, DMSO, d6) δ 9.24 (s, 1H), 7.25 (m, 1H), 7.10 (m, 3H), 6.64 (d, 2H, J=8.08 Hz), 6.55 (t, 1H, J=7.12 Hz), 6.22 (m, 1H), 4.68 (m, 2H), 2.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)(O[C@@H:18]([CH2:21]C(C)(C)C)[CH2:19]O)N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/[N:52]=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:52][C@@H:18]([CH3:21])[CH2:19][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Reactant: CC(C)(C)C[C@@H](CO)OC(N)=O
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Yield: 50.9 %

Procedure:
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (4.00 g; 19.64 mmol), (S)-tert-butyl-1-hydroxypropan-2-yl carbamate (3.79 g; 21.61 mmol) and triphenylphosphine were dissolved in dry THF under nitrogen atmosphere and stirred. Diisopropylazodicarboxylate (7.74 ml; 39.3 mmol) was added dropwise and the reaction flask was cooled by ice bath. The reaction was stirred at RT overnight (18 h) and evaporated to dryness. For Boc deprotection 200 ml of 10% HCl/EtOH solution was added to the evaporation residue, stirred for 20 h at RT and evaporated to dryness. 100 ml of water was added to the evaporation residue and washed with 3×120 ml of DCM to remove reactant residues. pH of water phase was adjusted to ˜12 by addition of 2 M NaOH, washed with 3×80 ml of DCM and organic phase dried over Na2SO4. Organic phase was filtered and evaporated to give 2.605 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](Cl)[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4].[NH3:13]>>[NH2:13][C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:10]=1
Reactant: N
Reactant: CCCCc1nc(C)cc(Cl)n1
Product: CCCCc1nc(C)cc(N)n1

Procedure:
The title compound is prepared from 2-n-butyl-4-chloro-6-methylpyrimidine (from Example 26) upon treatment with alcoholic ammonia as described by Marshall and Walker (J. Chem. Soc., 1951, 1004).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:26])[C:7]2[N:8]([CH:23]=[N:24][CH:25]=2)[C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]1)(=[O:3])[CH3:2].Cl.[C:28]1(=O)[CH2:31]C[CH2:29]1.C([BH3-])#N.[Na+]>O1CCOCC1.C(#N)C.O1CCCC1>[Cl:26][C:6]1[C:7]2[N:8]([CH:23]=[N:24][CH:25]=2)[C:9]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:31][CH2:28][CH2:29]3)[CH2:12][CH2:11]2)=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: O=C1CCC1
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C2CCC2)CC1
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
tert-Butyl 4-(6-acetyl-8-chloroimidazo[1,5-a]pyridine-5-yl)piperazine-1-carboxylate (33 mg, 0.087 mmol) was treated with a solution of 4 M hydrogen chloride in 1,4-dioxane (1.0 mL) and evaporated to dryness. Cyclobutanone (13 μL, 0.18 mmol), tetrahydrofuran (0.5 mL) and acetonitrile (0.5 mL) were added and the mixture was stirred for 30 minutes. Sodium cyanoborohydride (17 mg, 0.26 mmol) was added and was stirred for 4 hours. Purification by preparative LCMS (pH 10) gave the desired compound (18 mg, 61%). LCMS calculated for C17H22ClN4O (M+H)+: m/z=333.1. found: 332.9.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]([OH:17])(=[O:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15].[CH:18]1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(S([O-])(=O)=O)=CC=2C(C)C)CCCCC1.[Na+].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH3:18][O:16][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cccc(Cl)c1
Reactant: C#CCCCC(=O)O
Reactant: CC(C)c1cc(S(=O)(=O)[O-])cc(C(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CCCC#Cc1cccc(OC)c1
Yield: 688.8 %

Procedure:
The general procedure described in Example 27 was used with 3-chloroanisole (0.061 mL, 0.50 mmol), 5-hexynoic acid (0.072 mL, 0.65 mmol), PdCl2(CH3CN)2 (3.2 mg, 0.0125 mmol, 1.25 mol %), sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (20.0 mg, 0.0375 mmol, 3.75 mol %), Cs2CO3 (650 mg, 2.00 mmol), water (1.0 mL), acetonitrile (1.0 mL), 10 h, 100° C. The product was isolated as a colorless oil (60 mg, 85%). 1H NMR (400 MHz, CDCl3) δ: 7.16 (t, 1H, J=8.0 Hz), 6.96 (dt, 1H, J=1.2 Hz, 7.6 Hz), 6.89 (m, 1H), 6.80 (qd, 1H, J=1.2 Hz, 2.4 Hz, 8.4 Hz), 3.76 (s, 3H), 3.66 (s, 3H), 2.48 (t, 2H, J=7.2 Hz), 2.45 (t, 2H, J=6.8 Hz), 1.90 (q, 2H, J=6.8 Hz). 13C NMR (125 MHz, CDCl3) δ: 173.8, 159.4, 129.5, 124.9, 124.3, 116.6, 114.5, 88.9, 81.6, 55.4, 51.8, 33.1, 24.1, 19.1. IR (neat, cm−1): 2952, 2232, 1737, 1598, 1574, 1481, 1434, 1316, 1287, 1206, 1164, 1045, 854, 786, 688. 1H NMR (CDCl3) is shown in FIG. 8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[Si](C)(C)C)=[O:5])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[Cl:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccoc1[Si](C)(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)c1ccoc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
2-Trimethylsilyl-3-furancarboxylic acid (16.4 g) (synthesized in accordance with the method described in J. C. S. Perkin, 1, 1125 (1981)) was dissolved in N,N-dimethylformamide (50 ml), and potassium carbonate (12.3 g) and iodoethane (13.9 g) were added. The mixture was stirred at room temperature for 15 hours, poured into ice water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) as oil. 2-Trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) was dissolved in acetonitrile (75 ml), and sulfuryl chloride (10.9 g) in acetonitrile (25 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-chloro-3-furancarboxylic acid ethyl ester (3.5 g) as oil. 2-Chloro-3-furancarboxylic acid ethyl ester (3.5 g) was dissolved in ethanol (25 ml), and 1N aqueous sodium hydroxide (25 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with diisopropyl ether-hexane to give 2-chloro-3-furancarboxylic acid (2.2 g) as crystals. mp 138°-141° C.