Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:28])[N:11]2[C:16]=1[C:15]([N:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH3:18])=[N:14][CH:13]=[N:12]2.C([Li])CCCCC.Br[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:17]([CH3:18])[C:15]2[C:16]3=[C:8]([C:3]4[CH:4]=[N:5][N:6]([CH3:7])[C:2]=4[C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=4)[N:9]=[C:10]([CH3:28])[N:11]3[N:12]=[CH:13][N:14]=2)=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: COc1ccc(CN(C)c2ncnn3c(C)nc(-c4cnn(C)c4Br)c23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(C)c2ncnn3c(C)nc(-c4cnn(C)c4-c4ccc(C(F)(F)F)cn4)c23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-N-(4-methoxybenzyl)-N,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-amine (3.35 g, 7.57 mmol) in tetrahydrofuran (75 mL) was cooled to −78° C. and treated over 5 minutes with n-hexyllithium (2.3 M solution in hexane, 3.46 mL, 7.96 mmol). The reaction mixture was stirred for 30 minutes, and then treated in one portion with a −78° C. solution of zinc chloride (99.5%, 1.30 g, 9.49 mmol) in tetrahydrofuran (20 mL). After stirring for 5 minutes at −78° C., the reaction was warmed to room temperature over 30 minutes. After addition of 2-bromo-5-(trifluoromethyl)pyridine (2.57 g, 11.4 mmol), the reaction mixture was heated to 50° C., treated with tetrakis(triphenylphosphine)palladium(0) (99.9%, 87.9 mg, 0.076 mmol), and maintained at reflux for 4 hours. The reaction was cooled and concentrated in vacuo; the residue was dissolved in ethyl acetate and washed sequentially with water, saturated aqueous ammonium chloride solution, and saturated aqueous sodium bicarbonate solution. After drying over magnesium sulfate, the product solution was filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided a pale yellow oil (2.3 g), which was crystallized from heptane to afford the product as a white powder. Yield: 1.58 g, 3.11 mmol, 41%. APCI m/z 509.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.54 (s, 3H), 2.72 (s, 3H), 3.76 (s, 3H), 4.14 (s, 3H), 4.34 (br s, 2H), 6.76 (br d, J=8.8 Hz, 2H), 6.94 (br d, J=8.5 Hz, 2H), 7.39 (d, J=8.3 Hz, 1H), 7.72 (s, 1H), 7.76 (dd, J=8.4, 2.2 Hz, 1H), 7.85 (s, 1H), 8.94-8.96 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].Cl>>[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.20) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 527.2 [(M+H)+]; mp 223° C.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1COCC1.BrCCOC[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:7]([O:9][CH2:10][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCCCC1
Reactant: BrCCOCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(COCc2ccccc2)cc1
Yield: 88.3 %

Procedure:
Using Methyl cyclohexanecarboxylate (5.55 g), KHMDS (100 ml of a 0.5M solution in toluene), anhydrous THF (100 ml) and benzyl 2-bromoethyl ether (10.09 g) and the procedure set forth previously (Example 108, Step 1), the desired intermediate benzyl ether (6.83 g) was obtained after silica gel column chromatography (EtOAc:Hexanes: 15:85).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH2:14]([C@@H:21]1[CH2:25][O:24][C:23](=[O:26])[NH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1(C)C=CC=CC=1>[CH2:14]([C@@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][CH:8]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccc(C2CC2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(C2CC2)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
2-(4-Cyclopropylphenyl)acetic acid (2.82 g, 16.003 mmol) was combined with (R)-4-benzyloxazolidin-2-one (3.4030 g, 19.204 mmol) in toluene (14 mL). The suspension was treated with triethylamine (6.6917 mL, 48.010 mmol) and then heated to 80° C. The solution was treated dropwise with a solution of pivaloyl chloride (1.9893 mL, 16.003 mmol) in toluene (3.5 mL). The reaction was heated overnight at 80° C. The reaction was cooled and washed with 2N HCl and then separated. The aqueous layer was washed with toluene, and the combined organics were then washed with 2N HCl, water, saturated NaHCO3 (2×), saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product was subjected to chromatography on SiO2 eluting with 9:1 hexanes/ethyl acetate to yield (R)-4-benzyl-3-(2-(4-cyclopropylphenyl)acetyl)oxazolidin-2-one (3.43 g, 64%). 1H NMR (CDCl3, 400 MHz) δ 7.33-7.20 (m, 5H), 7.16-7.11 (m, 2H), 7.05 (d, J=8.2, 2H), 4.70-4.63 (m, 1H), 4.32-4.14 (m, 4H), 3.26 (dd, J1=3.2, J2=13.3, 1H), 2.75 (dd, J1=9.5, J2=13.3, 1H), 1.93-1.85 (m, 1H), 0.98-0.92 (m, 2H), 0.72-0.66 (m, 2H).
Reaction SMILES: CO[C:3](=[O:21])[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH:10]([CH2:18][O:19][CH3:20])[CH2:9][N:8]3[CH:7]=1)=O.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][C:33]([NH2:35])=[O:34])=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[CH3:20][O:19][CH2:18][CH:10]1[CH2:11][C:12]2[C:17]3=[C:16]([C:6]([C:4]4[C:3](=[O:21])[NH:35][C:33](=[O:34])[C:32]=4[C:27]4[C:26]5[C:30](=[CH:31][C:23]([F:22])=[CH:24][CH:25]=5)[NH:29][CH:28]=4)=[CH:7][N:8]3[CH2:9]1)[CH:15]=[CH:14][CH:13]=2
Reactant: COCC1Cc2cccc3c(C(=O)C(=O)OC)cn(c23)C1
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Product: COCC1Cc2cccc3c(C4=C(c5c[nH]c6cc(F)ccc56)C(=O)NC4=O)cn(c23)C1

Procedure:
Beginning with (5-methoxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester and (6-fluoro-1H-indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[N+](C1C=CC(C(O[C@@H]2CC3C(=CC=CC=3)[C@H]2NC2C(CC)=NC(C3C=CC(Cl)=CC=3Cl)=C(CC)N=2)=O)=CC=1)([O-])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1O
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@H]1O

Procedure:
Following the procedure for the preparation of (1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting (1R,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl 4-nitrobenzoate and making non-critical variations provided the title compound as an off-white solid. IR (diffuse reflectance) 3326, 2976, 1572, 1550, 1503, 1472, 1449, 1435, 1399, 1358, 1198, 1074, 862, 819, 753 cm−1; OAMS supporting ions at: ESI+ 428.1; MS (EI) m/z 427 (M+); HRMS (FAB) calcd for C23H23CL2N3O+H1 428.1296, found 428.1295. [α]25D=112 (c 0.58, methylene chloride). Anal. Calcd for C23H23Cl2N3O: C, 64.49; H, 5.41; N, 9.81. Found: C, 64.60; H, 5.34; N, 9.75.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4].[C:22](O)(=[O:24])C>C=O>[CH2:1]([N:5]1[C:9]([CH2:22][OH:24])=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]=[C:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCn1cc(-c2ccccc2)nc1-c1ccccc1
Agent: C=O
Product: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CO

Procedure:
1-Butyl-2,4-diphenylimidazole (3 g) is dissolved in 50 ml of acetic acid with 50 ml of 37% aqueous formalin solution. The mixture is heated at reflux for 48 h, cooled and the solvents evaporated. The residue is triturated with ether and filtered. The filtrate is concentrated and partitioned between ethyl acetate (100 mL) and 5% aqueous acetic acid (100 mL). The aqueous layer is extracted with ethyl acetate (100 mL). The combined organic extracts are washed with 1N NaOH solution, brine, dried over Na2SO4, and concentrated. The crude product is triturated with ethyl acetate to give the product as a white solid. 1H NMR (CDCl3) 7.73 (d, J=5 Hz, 2H), 7.62 (d, J=4 Hz, 2H), 7.3–7.5 (m, 6H), 4.82 (s, 2H), 4.10 (t, J=7 Hz, 2H), 1.7 (m, 2H), 1.25 (m, 2H), 0.85 (t, J=7 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9]2)=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:17]1([CH:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)([CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:9]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1=C(c2ccccc2)c2ccccc2C1(Cc1ccncc1)Cc1ccncc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(C2CC(Cc3ccncc3)(Cc3ccncc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-bis(4-pyridinylmethyl)-3-phenyl-1H-indene (5.8 g, 15.5 mmol) in 95% ethanol (100 ml), was added 5% palladium on carbon catalyst (1.45 g) and the mixture was shaken under hydrogen (50 psig) at room temperature for 2 h. The catalyst was removed by filtration, and the solvent removed by rotary evaporation. The oil was purified via column chromatography (silica gel, 10% methanol/dichloromethane) to give pure 4-((2,3-dihydro-3-phenyl-1-(4-pyridinylmethyl)-1H-inden-1-ylmethyl))pyridine. NMR (200 MHz, CDCl3) δ2.05 (dd, 1H); 2.38 (dd, 1H); 2.93 (dd, 2H); 3.15 (dd, 2H); 3.42 (m, 1H); 6.67 (dd, 4H); 7.00 (d, 2H); 7.10-7.34 (m, 7H); 8.36 (d, 2H, J=5Hz); 8.42 (d, 2H, J=5Hz). Mass Calcd. for C27H24N2 : 376.1937. Found: 376.1951.
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:20]=[CH:19][C:18]=23)=[O:13])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:29][C:30]1([CH3:38])[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH2:36][NH2:37].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:29][C:30]1([CH3:38])[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH2:36][NH:37][C:6]([C:5]1[CH:9]=[C:10]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:20]=[CH:19][C:18]=23)=[O:13])[C:2]([CH3:1])=[N:3][CH:4]=1)=[O:8]
Reactant: Cc1ncc(C(=O)O)cc1NC(=O)c1cnn2cc(-c3cnn(C)c3)ccc12
Reactant: CC1(C)CCCN1CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(C(=O)NCCN2CCCC2(C)C)cc1NC(=O)c1cnn2cc(-c3cnn(C)c3)ccc12
Reaction time: 1.5 h

Procedure:
6-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)nicotinic acid (6.6 g, 1.1 equiv) and 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.397 g, 11.14 mmol) were combined in DMF (100 ml) and treated with DIPEA (8.34 ml, 47.7 mmol) followed by HATU (4.44 g, 11.67 mmol). After stiring at RT for 90 mins, the mixture was partitioned between water (1 L) and EtOAc (750 ml). The resulting suspension was removed by filtration and the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4, filtered and evaporated to dryness. Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].O.CO.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(CC(C)(C)O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(O)Cc1ccc(C(=O)O)cc1F
Temperature: 55 °C
Yield: 67 %

Procedure:
Methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoate (1.59 g, 7.03 mmol) was dissolved in THF (40 mL), water (200 mL) and MeOH (21 mL) before LiOH (1.01 g, 42.2 mmol) was added. The reaction mixture was heated at 55° C. for 30 minutes. The reaction mixture was cooled to room temperature and the solvents were removed under reduced pressure. The residue was dissolved in water and cooled in an ice water bath and treated with HCl 1M to pH 3. The resulting precipitate was collected by vacuum filtration, washed with water and dried under high vacuum to yield 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoic acid (999 mg, 67%) as a white solid. ESI-MS m/z calc. 212.1, found 211.1 (M+1)+; Retention time: 0.98 minutes (3 min run, scanned using negative ionization mode). 1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J=7.9, 1.6 Hz, 1H), 7.77 (dd, J=10.1, 1.6 Hz, 1H), 7.39 (d, J=15.1 Hz, 1H), 2.91 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]#[C:6][C:7](O)([CH3:9])[CH3:8])[CH3:2].CCN(S(F)(F)[F:18])CC>ClCCl>[CH2:1]([O:3][C:4](=[O:11])[C:5]#[C:6][C:7]([F:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)C#CC(C)(C)O
Solvent: ClCCl
Product: CCOC(=O)C#CC(C)(C)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
A solution of 4-hydroxy-4-methyl-pent-2-ynoic acid ethyl ester (4.9 g, 155 mmol) in dichloromethane (30 mL) was cooled to −78° C. and treated with DAST (5.3 g, 161.2 mmol) the reaction mixture was stirred for 2 h at −78° C. then warmed to room temperature and poured over ice. After the ice had melted, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (sodium sulfate) and concentrated on a rotary evaporator to provide 5.0 g (100%) of 4-fluoro-4-methyl-pent-2-ynoic acid ethyl ester as a brown oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH2:5].[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]>>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCCCO
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCO)n4)cc3)cc12

Procedure:
Using 3-hydroxy-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.73 (t, 2H, J=7 Hz); 2.98 (t, 2H, J=7 Hz); 3.40 (m, 2H); 4.48 (bs, 1H); 7.20 (m, 3H); 7.48 (m, 2H); 7.92 (d, 2H, J=8 Hz); 8.18 (m, 3H); 8.37 (bd, 1H, J=5 Hz); 8.68 (bt, 1H); 12.12 (bs, 1H). MS (ion spray) m/z 441 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:22][CH3:23])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:6]([N:8]1[CH:14]2[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7].[Cl-:24].[NH4+]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[Cl:24][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:17]([O:18][CH2:19][C:20]#[CH:21])=[C:16]([O:22][CH3:23])[CH:15]=1
Reactant: C#CCOc1c(OC)cc(C(=O)N2C3CCCCC32)cc1OC
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: C#CCOc1c(OC)cc(C(=O)NC2CCCCC2Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2 ml of chloroform and 258 mg of zinc (II) chloride was stirred at room temperature for 5 minutes. Thereafter, a mixture of 300 mg of 7-[3,5-dimethoxy-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane and 2 ml of chloroform was added dropwise thereto at room temperature, and the resulting mixture was stirred at room temperature for 5 hours. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and this was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.16 g of N-(2-chlorocyclohexyl)-3,5-dimethoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 109 of the present invention) represented by the formula:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[N:31](C4CCCCO4)[N:30]=[CH:29][CH:28]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[CH:28]=[CH:29][NH:30][N:31]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccnn2C2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Alternatively, Example 2 was prepared by treating a suspension of 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.1, 68.3 g, 132 mmol) in DCM (1 L) with TFA (305 mL, 3959 mmol) at RT for 5.5 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc (2 L), washed with a sat. solution of NaHCO3 (3×500 mL) and brine (2×500 mL), and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the residue was suspended in DCM (300 mL) and stirred at RT for 15 min. The crystalline material was filtered, washed with DCM (200 mL), dried under reduced pressure, dissolved in MeOH (500 mL) and treated with Si-Thiol (Biotage, 10.0 g, 13 mmol) for 15 h at 30° C. The mixture was filtered and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel, 2 kg, DCM/MeOH 95:5) and crystallized from MeCN to afford the title compound as a white crystalline solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[NH:10])[NH2:9])[N:3]=1.C([O:13][CH:14]=[C:15]([C:21](OCC)=O)[C:16]([O:18]CC)=[O:17])C.C[O-].[Na+].[OH-].[K+]>CO>[OH:13][C:14]1[C:15]([C:16]([OH:18])=[O:17])=[CH:21][N:9]=[C:8]([C:4]2[N:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)c1cccnn1
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cnc(-c2cccnn2)nc1O

Procedure:
A mixture of crude Pyridazine-3-carboximidamide hydrochloride, 30-id, (4.2 g, 34.4 mmol), diethyl ethoxymethylenemalonate (6.5 mL, 34.4 mmol) and sodium methoxide (1.85 g, 41.3 mmol) in MeOH (100 mL) was refluxed overnight. The reaction mixture was added with KOH (3.8 g, 68.8 mmol) and refluxed for 4 h. The reaction was concentrated. The residue was dissolved with water (30 mL) and extracted with EtOAc. The aqueous layer was adjusted to pH=2 by addition of concentrated aq. HCl. The solids was filtered and rinsed with water and hexane to afford the title compound, 30-ie, (3 g, 40%). 1H NMR (300 MHz, CD3OD) δ14.7 (s, 1H), 9.50 (dd, J=1.6, 5.0 Hz), 8.57 (s, 1H), 8.51 (dd, J=1.6, 8.4 Hz, 1H), 8.01 (dd, J=5.0, 8.4 Hz, 1H), 3.44 (s, 1H). LC-MS: (M+H)+ 219.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[CH3:14])=[N:5][S:4][N:3]=1.C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:6]1[C:2]([Cl:1])=[N:3][S:4][N:5]=1
Reactant: Cc1cc(Cl)ccc1-c1nsnc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2nsnc2Cl)c(CBr)c1

Procedure:
A mixture of 3-chloro-4-(4-chloro-2-methylphenyl)-1,2,5-thiadiazole (0.211 g, 0.86 mmol), NBS (0.153 g, 0.86 mmol) and benzoyl peroxide (10.4 mg, 0.04 mmol) in carbon tetrachloride (5.0 mL) were refluxed for 1 h. More benzoyl peroxide (10.4 mg, 0.04 mmol) was added and the solution was refluxed for a further 16 h. The resulting suspension was filtered, rinsing with ether. The filtrate was washed with 10% aqueous sodium sulfite, saturated aqueous sodium bicarbonate solution and brine. The ether layer was separated, dried (Na2SO4) and reduced in vacuo. The residue was purified by flash chromatography on silica (eluting with EtOAc/hexanes gradient, 1–3% EtOAc). 3-[2-(Bromomethyl)-4-chlorophenyl]-4-chloro-1,2,5-thiadiazole was isolated as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 4.51 (s, 2H), 7.43 (s, 2H), 7.55 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[C:12]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[N:11]=[C:10]2[C:6]=1[NH:7][C:8](=[O:31])[N:9]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])=O.[NH2:32]C1C(C(OC)=O)=NC(N2C3C=CC=CC=3N=C2)=NC=1NC1C=CC=CC=1OC.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[N:14]1([C:12]2[N:11]=[C:10]3[C:6]([NH:7][C:8](=[O:31])[N:9]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:5]([C:3]([NH2:32])=[O:2])[N:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: COC(=O)c1nc(-n2cnc3ccccc32)nc(Nc2ccccc2OC)c1N
Reactant: COC(=O)c1nc(-n2cnc3ccccc32)nc2c1[nH]c(=O)n2-c1ccccc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(-n3cnc4ccccc43)nc21
Yield: 62 %

Procedure:
Methyl-2-(1H-benzo[d]imidazol-1-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. A solution of methyl 5-amino-2-(1H-benzo[d]imidazol-1-yl)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.300 g, 0.769 mmol), 1,1′-carbonyldiimidazole (0.311 g, 1.922 mmol), and dichloromethane (10 mL) was reacted as described in General Procedure F. The reaction mixture was filtered to give the titled compound as white solid (0.200 g, 62%). 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.44-8.41 (m, 1H), 7.76-7.73 (m, 1H), 7.64-7.55 (m, 2H), 7.38-7.29 (m, 3H), 6.22-7.16 (m, 1H), 4.02 (s, 3H), 3.79 (s, 3H); MS (ESI) m/z 417.5 [M+1]+.