Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])N=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.F[C:38](F)(F)C1C=C(C=C(C(F)(F)F)C=1)C(O)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:38]=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=1
Reactant: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F
Yield: 8 %

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-fluoro-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine (example 159, intermediate) and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) after a reaction time of 40 hours. The compound was purified by two silica gel chromatographies using a 10 g column and 5 g column, respectively, on a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The resulting brown solid was suspended in tert-butyl methyl ether, filtered and washed with tert-butyl methyl ether to give the title compound as an off-white solid (8%). MS (ESI): m/z=535.09 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:9])[CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]1.CCN(CC)CC>CC(O)C>[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)=[O:9])[CH:3]=2)[CH2:27][CH2:28]1)(=[O:34])[CH3:33]
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Reactant: CC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)N1CCC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ncn2)CC1
Yield: 130573.4 %

Procedure:
The solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (190 g, 0.55 mmol) and 1-(4-aminopiperidin-1-yl)ethanone (78 g), Et3N (100 g, 1 mol) in i-PrOH (2000 mL) was stirred at 60° C. for 16 h, at which time LCMS showed completed conversion. The mixture was concentrated and the residue was purified by flash chromatography to give the crude product. Four batches were run in parallel and produced a combined crude product weight of 482 g. This crude was further purified on preparative HPLC to give the title compound (325 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 8.26 (s, 1H), 7.15-7.02 (m, 5H), 4.46 (m, 1H), 4.15-4.07 (m, 2H), 3.88 (m, 1H), 3.74 (s, 2H), 3.53 (m, 2H), 3.33 (m, 1H), 2.95-2.86 (m, 5H), 2.68 (m, 2H), 2.14-2.01 (m, 5H), 1.48-1.42 (m, 2H); LCMS (m/z): 453.3 [M+H]+
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][CH:22]([F:24])[F:23])=[CH:15][N:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[F:23][CH:22]([F:24])[CH2:21][O:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[C:7]=3[CH2:8]2)=[N:14][CH:15]=1
Reactant: O=COc1ccccc1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)F
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ncc1OCC(F)F
Yield: 68 %

Procedure:
The title compound is prepared in 68% yield (200 mg, pale brown solid) from 4-chloro-2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (240 mg, 0.68 mmol, Intermediate-69) and phenyl formate (170 mg, 1.4 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12](=[NH:13])[O:16][CH2:14][CH3:15])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CCO
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCOC(=N)Cc1ccc([N+](=O)[O-])cc1
Yield: 47 %

Procedure:
Hydrogen chloride gas was passed through a solution of 4-nitrophenyl acetonitrile (5.0 g, 30.8 mmol) in ethanol (400 mL) until saturation, keeping the temperature between 0-5° C. The solvent was removed under reduced pressure at 15° C. to give a residue which on trituration with diethyl ether gave a solid. The solid was filtered under a nitrogen atmosphere and washed thoroughly with diethyl ether. Drying under vacuum afforded ethyl 2-(4-nitrophenyl)-acetimidate hydrochloride (3.5 g, 47%) which was hygroscopic in nature.
Reaction SMILES: [CH2:1]1[CH2:15][C@H:14]2[C@@H:4]([CH2:5][C:6]3[C:16]4[C:9](=[CH:10][CH:11]=[CH:12][C:13]2=4)[NH:8][CH:7]=3)[NH:3][CH2:2]1.[C:17](OC(=O)C)(=[O:19])C.C([O-])(=O)C.[Na+].N>C(O)(=O)C>[OH:19][CH2:17][C:7]1[NH:8][C:9]2[C:16]3[C:6]=1[CH2:5][C@@H:4]1[C@@H:14]([C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:1][CH2:2][NH:3]1
Reactant: CC(=O)OC(C)=O
Reactant: c1cc2c3c(c[nH]c3c1)C[C@H]1NCCC[C@H]21
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1[nH]c2cccc3c2c1C[C@H]1NCCC[C@H]31
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 mmol of ergoline is dissolved in 10 ml of glacial acetic acid. 5 ml (0.05 mol) of acetic anhydride and 0.8 g (0.01 mol) of anhydrous sodium acetate are added and allowed to stir overnight at room temperature. For working up, ice is added, it is stirred for 30 minutes and mixed with NH3 solution. After extraction with dichloromethane, drying of the organic phases on Na2SO4 and removal of the solvent in a vacuum, the raw product is obtained which is further purified by crystallization or chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:9]Cl>>[C:4](=[O:8])([O:5][CH:6]([Cl:9])[CH3:7])[O:3][CH2:1][CH3:2]
Reactant: ClCl
Reactant: CCOC(=O)OCC
Product: CCOC(=O)OC(C)Cl
Yield: 42.9 %

Procedure:
Into the same flask as used in Example 1, 236.6 grams (2 moles) of pure diethylcarbonate were added, and then 2.6 moles of chlorine gas were introduced into the flask over a five hour period at a range of 50° C. to 52° C. under the irradiation of ultraviolet rays. When the reaction was completed, the unreacted diethylcarbonate was removed by subjecting it to fractional distillation to yield 131 grams of ethyl α-chloroethyl carbonate. B.P.: 160°-163° C.; Yield: 59.8% to the consumed diethylcarbonate. The data of the IR and the NMR were identified to be the same as those in Example 1.
Reaction SMILES: [CH2:1]([Si:4]([Cl:7])(Cl)Cl)[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.[CH3:19][O:20][C:21]([CH3:32])([C@H:23]([OH:31])[C@@H:24]([OH:30])[C:25]([O:28][CH3:29])([CH3:27])[CH3:26])[CH3:22]>C(Cl)Cl>[CH2:1]([Si:4]1([Cl:7])[O:30][C@@H:24]([C:25]([O:28][CH3:29])([CH3:26])[CH3:27])[C@H:23]([C:21]([CH3:32])([O:20][CH3:19])[CH3:22])[O:31]1)[CH:2]=[CH2:3]
Reactant: COC(C)(C)[C@H](O)[C@@H](O)C(C)(C)OC
Reactant: C=CC[Si](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC[Si]1(Cl)O[C@@H](C(C)(C)OC)[C@H](C(C)(C)OC)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
Preparation of (4R,5R)-2-allyl-2-chloro-4,5-bis-(1-methoxy-1-methyl-[1,3,2]dioxasilolane: To a cooled (0° C.) solution of allyltrichlorosilane (7.0 mL; 48 mmol) in CH2Cl2 (80 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (15 mL; 102 mmol). A solution of (3R,4R)-2,5-dimethoxy-2,5-dimethyl-hexane-3,4-diol (10.0 g; 48 mmol) in CH2Cl2 (80 mL) was then added and the mixture was allowed to warm to ambient temperature and stirred for 12 hours. The solution was concentrated and the residue was treated with diethylether (100 mL). The mixture was stirred for 1 hour. The mixture was then filtered and the filtrate was concentrated. The residue was distilled under reduced pressure to give 6.6 g (44%) of (4R,5R)-2-allyl-2-chloro-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolane as a clear, colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]=1[NH2:8].[OH:18][C:19]1[C:20]([CH3:35])=[C:21]2[C:26](=[C:27]([CH3:30])[C:28]=1[CH3:29])[O:25][C:24]([CH3:34])([C:31](O)=[O:32])[CH2:23][CH2:22]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[NH2:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[N:4]([CH3:16])[C:3](=[O:17])[C:2]=1[NH:1][C:31]([C:24]1([CH3:34])[CH2:23][CH2:22][C:21]2[C:26](=[C:27]([CH3:30])[C:28]([CH3:29])=[C:19]([OH:18])[C:20]=2[CH3:35])[O:25]1)=[O:32]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: Cn1c(=O)c(N)c(N)n(-c2ccccc2)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)Nc1c(N)n(-c3ccccc3)c(=O)n(C)c1=O)O2
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 5,6-diamino-3-methyl-1-phenyl-2,4 (1H, 3H) -pyrimidinedione (3.02 g, 13 mmol), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (3.58 g, 14.3 mmol) and 4-(dimethylamino)pyridine (0.32 g, 2.6 mmol) was suspended in dichloromethane (60 mL). To the resultant suspension was added dropwise a solution of N, N'-dicyclohexylcarbodiimide (2.82 g, 13.7 mmol) indichloromethane (60 mL) at room temperature. The reaction mixture was stirred overnight and then filtered. The filtrate was concentrated and then subjected to silica-gel column chromatography, thereby giving the title compound (yield 57%). TOF-MS (Time-of-flight type mass spectrum): m/z 465 [M+H]+1H-NMR (CDC13):δ1.60(3H, s), 1.90-2.04(1H, m), 2.08(3H, s), 2.18(3H, s), 2.29(3H, s), 2.30-2.38(1H, m), 2.54-2.64(2H, m), 3.34(3H, s), 4.32(1H, s), 5.17(2H, bs), 7.27-7.36(2H, m), 7.53-7.60 (3H, m), 8.41 (1H, bs)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH:7]1([C:10]2[C:11]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4[CH:32]=[CH:31][C:30](I)=[CH:29][C:28]=4[F:34])=[O:26])[CH2:21][CH2:20]3)=[N:12][CH:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[CH2:9][CH2:8]1>>[CH:7]1([C:10]2[C:11]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[CH:29][C:28]=4[F:34])=[O:26])[CH2:23][CH2:24]3)=[N:12][CH:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[CH2:8][CH2:9]1
Reactant: O=C(c1ccc(I)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1CCCN1
Product: O=C(c1ccc(N2CCCC2=O)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 63 %

Procedure:
Using pyrrolidin-2-one (35 mg) and [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (200 mg) described in Preparation Example 164 and by the reaction and treatment in the same manner as in Example 1, the title compound (115 mg) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([S:7][CH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]2[C:10]=1[NH:11][C:12](=[O:20])[CH2:13][NH:14]2)=[O:6])C.O.[OH-].[Li+]>O1CCCC1.O>[Br:19][C:17]1[CH:16]=[C:15]2[C:10]([NH:11][C:12](=[O:20])[CH2:13][NH:14]2)=[C:9]([CH2:8][S:7][C:5](=[O:6])[C:4]([OH:21])=[O:3])[CH:18]=1
Reactant: CCOC(=O)C(=O)SCc1cc(Br)cc2c1NC(=O)CN2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CNc2cc(Br)cc(CSC(=O)C(=O)O)c2N1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
500 mg (1.34 mmol) of 7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethylsulfanylacetic acid ethyl ester (Example 18) are suspended in 20 ml of tetrahydrofuran and 10 ml of water, and 225 mg (4 equiv.) of lithium hydroxide hydrate are added. The mixture is stirred at 20° C. for 48 hours. The tetrahydrofuran is concentrated by evaporation, 60 ml of water are added and the solution is acidified with 1 N hydrochloric acid. The solid is filtered off, washed with water and dried.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:13]([C:14](=[O:16])[CH3:15])=[C:9]3[CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C(O[CH:30](OC(C)(C)C)[N:31]([CH3:33])[CH3:32])(C)(C)C>O>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[C:13]([C:14](=[O:16])/[CH:15]=[CH:30]/[N:31]([CH3:33])[CH3:32])=[C:9]3[CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: COc1ccc(-c2nn3c(NC4CC4)cccc3c2C(C)=O)cc1
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A solution of 1-[7-(cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (1.22 g, 3.8 mmol) in N,N-dimethylformamide di-tert-butyl acetal (8 mL, 33 mmol) was heated under reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 hexanes-ethyl acetate to ethyl acetate) provided (2E)-1-[7-(cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (1.19 g, 83%) as a gold foam. 1H NMR (CDCl3): δ 7.73 (d, 1 H), 7.62 (d, 2 H), 7.34 (t, 1 H), 6.97 (d, 2 H), 6.37 (d, 1 H), 6.29 (s, 1 H), 5.13 (d, 1 H), 3.85 (s, 3 H), 2.95 (broad, 3 H), 2.65 (m, 1 H), 2.50 (broad, 3 H), 0.86 (m, 2 H), 0.72 (m, 2 H); MS m/z 377 (M+1).
Reaction SMILES: [NH2:1][C:2](=[NH:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1CCN2C(=NCCC2)CC1.C(O[CH:24]=[CH:25][C:26](=O)[C:27]([F:30])([F:29])[F:28])C>C(#N)C>[NH2:9][C:2]1[N:1]=[C:26]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:24][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: CCOC(=O)CC(=N)N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(F)(F)F)nc1N
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
19.5 g (0.12 mol) of ethyl 3-amino-3-iminopropanoate (described in Chemical and Pharmaceutical Bulletin, vol. 43, No. 5, p. 793 (1995)) was added to 100 mL of acetonitrile, and 18.6 g (0.12 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto at room temperature. The resulting mixture was stirred for 5 minutes. 20.6 g (0.12 mol) of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one was added to the above mixture, and 18.6 g (0.12 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto. The resulting mixture was stirred for 3 hours at 80° C. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was concentrated to half the original volume. Ice water was added thereto. Crystals precipitated therefrom were separated by filtration, and were dissolved in ethyl acetate. The filtrate was extracted with ethyl acetate. The solution having the crystals dissolved therein and the organic phase extracted were combined, and the resultant was washed with brine, and then was dried and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:9 to 1:4), and thus 17.8 g of the title compound was obtained as colorless crystals (yield: 62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8](=O)[NH:9][CH:10]=1)=[O:4].P(Cl)([Cl:25])(OC1C=CC=CC=1)=O>>[CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8]([Cl:25])=[N:9][CH:10]=1)=[O:4]
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: COC(=O)c1c[nH]c(=O)c2ccn(C)c12
Product: COC(=O)c1cnc(Cl)c2ccn(C)c12

Procedure:
1-Methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid methyl ester (1.25 g) and phenyl dichlorophosphate (12 ml) were heated at 180° C. under argon for 30 minutes. The reaction was allowed to cool at which point a precipitate formed. This was filtered off and washed with diethyl ether to yield the title compound as a grey solid (1.2 g).
Reaction SMILES: ClC1C(Cl)=CC=CC=1C1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[Na+].[I-].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1CCNCC1.CCN(C(C)C)C(C)C>CC#N>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Clc1cccc(C2CCN(CCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCOc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A mixture of intermediate 44 (42.2 mg, 0.17 mmol) and NaI (49.5 mg, 0.33 mmol) in CH3CN (3 mL) was heated to reflux for 30 min and then cooled to rt. To this mixture was added intermediate 65 (35.0 mg, 0.18 mmol), followed then by DIEA (0.063 mL, 0.36 mmol). The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by ISCO to give 6-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-1H-indazole (compound 50) (36.6 mg, 60%). HPLC: 99%, RT 3.907 min. MS (ESI) m/z 367.20 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:16][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(C)c2cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2ncnc(CBr)c2cc1OC
Temperature: 25 °C

Procedure:
4-Methyl-6,7-dimethoxyquinazoline (D-1) (3.43 g, 14.7 mMol), N-bromosuccinimide (NBS) (2.64 g, 14.7 mMol) and benzoyl peroxide (BPO) (500 mg) were heated under reflux in 200 mL of carbon tetrachloride with irradiation by a 200 W sun lamp for 5 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and extracted twice with water. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. Flash chromatography on silica gel, eluting with hexanes/ethyl acetate gave 4-bromomethyl-6,7-dimethoxyquinazoline (E-1) as a pinkish solid, 1.39 g; 1H NMR (CDCl3, 300 MHz) 9.07 (s, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 4.85 (s, 2H), 4.06 (s, 6H) ppm; 13C NMR (CDCl3, 75 MHz) 161.22, 156.32, 153.45, 150.72, 149.22, 118.85, 107.47, 101.78, 56.84, 56.70, 30.13; MS (ES) 283/285 (M+H).
Reaction SMILES: Cl.[CH2:2]([N:9]([C:17]1[CH:18]=[C:19]([CH:44]=[CH:45][CH:46]=1)[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:23]=1)=[O:21])C(OC(C)(C)C)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[CH2:2]([NH:9][C:17]1[CH:18]=[C:19]([CH:44]=[CH:45][CH:46]=1)[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:23]=1)=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(C(=O)c2cn(CCCC(=O)OCc3ccccc3)c3ccccc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCCn1cc(C(=O)c2cccc(NCc3ccccc3)c2)c2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
4N Hydrochloric acid in 1,4-dioxane (2 ml) was added to a solution of benzyl 4-[3-[3-[N-benzyl-N-(tert-butoxycarbonyl)amino]benzoyl]indol-1-yl]butyrate (0.31 g) in 1,4-dioxane (2 ml). The mixture was stirred at room temperature for 1 hour and evaporated. The residue was dissolved in ethyl acetate. The solution was washed wirh sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and evaporated to give benzyl 4-[3-(3-benzylaminobenzoyl)indol-1-yl]butyrate (258 mg) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>CN1CCCC1=O.C(OCC)(=O)C.P([O-])([O-])([O-])=O>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[N:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1cc2ccsc2c(Cl)n1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(C)cc3ccsc23)c(OC)c1
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-5-methyl-thieno[2,3-c]-pyridine (100 mg, 0.544 mmol) and 2,4-dimethoxybenzylamine (0.245 mL, 1.63 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was heated to 180° C. in an oil bath for 19 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and aqueous phosphate buffer (1.0 M, pH 7, 20 mL). The separated organics were sequentially washed with water (10 mL), aqueous phosphate buffer (1.0 M, pH 7, 10 mL), water (10 mL), and brine (10 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (5-25% ethyl acetate/hexanes, linear gradient) to give N-(2,4-dimethoxybenzyl)-5-methylthieno[2,3-c]pyridin-7-amine. MS ESI calc'd. for C17H19N2O2S [M+H]+ 315. found 315.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[O:14][C:15]([CH2:21][OH:22])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:23](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:20][C:16]1[C:17](=[O:19])[CH:18]=[C:13]([CH2:12][NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[O:14][C:15]=1[CH2:21][OH:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Reactant: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)oc(CO)c1O
Product: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)oc(CO)c1OCc1ccccc1
Yield: 24.88 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-3-chloro-benzenesulfonamide (10-05) (2.2 g, 24.88%) was synthesized as a white solid from 3-chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-05) (7.0 g, 20.29 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])=[O:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]([CH3:45])[CH3:46])=[O:39])=[CH:36][CH:35]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: CN(C)CCCNC(=O)c1ccc(N)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: CN(C)CCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCC2)CC(F)(F)C(=O)N3C)cc1
Yield: 87.5 %

Procedure:
A mixture of 0.0673 g (0.22 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0634 g (0.33 mmole) of toluenesulfonic acid monohydrate, 0.0492 g (0.22 mmole) of 4-amino-N-(3-dimethylamino-propyl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 22 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) to give 0.0938 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-benzamide (I-19)