Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH:14]=O)[CH:11]=3)[C:4]=2[NH:5][N:6]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][N:20]4[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]4)[CH:11]=3)[C:4]=2[NH:5][N:6]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc2c(c1)Cc1c(I)n[nH]c1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc3c(c2)Cc2c(I)n[nH]c2-3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 318 (980 mg, 3.16 mmol) in dichloromethane was added 1-methylpiperazine (0.83 mL, 7.5 mmol) and acetic acid (0.43 mL, 7.5 mmol) and the mixture was stirred at room temperature overnight. To this mixture was added sodium triacetoxyborohydride (1.0 g, 4.7 mmol) followed by methanol (5 mL) and stirring at room temperature was continued for about 2 days. The mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel using dichloromethane/methanol (9:1)+1% ammonium hydroxide as eluent to provide Example 607. MS (ESI): m/z 395 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][P:6]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1I)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[P:29]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])CCC.Cl>CN(C=O)C.[Cu]Cl>[CH2:1]([O:5][P:6]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[P:29]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOP(=O)(OCCCC)c1ccsc1I
Reactant: CCCCOP(=O)(OCCCC)c1ccsc1[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCOP(=O)(OCCCC)c1ccsc1-c1sccc1P(=O)(OCCCC)OCCCC
Temperature: 80 °C
Reaction time: 10 h
Yield: 55 %

Procedure:
At room temperature, 0.8045 g (2.00 mmols) of 3-(dibutoxyphosphoryl)-2-iodothiophene and 1.1308 g (2.00 mmols) of 2-(tributylstannyl)-3-(dibutoxyphosphoryl)thiophene were dissolved in DMF, to which 0.2376 g (2.40 mmols) of commercially available copper(I) chloride was added at room temperature. Thereafter, the reaction mixture was heated to 80° C. and stirred for 10 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a 10% hydrochloric acid aqueous solution, followed by extraction of the resulting product with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (gradiated from ethyl acetate:hexane=1:1 with acetone) to obtain the specified substance in the form of white crystals at a yield of 1.6012 g (yield: 55%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.S(C1C=CC(C)=CC=1)(O[CH2:30][CH:31]1[O:33][CH2:32]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:30][C@H:31]4[CH2:32][O:33]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
4-(4-Fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (339 mg, 1 mmol), (prepared as described for the starting material in Example 7), was dissolved in dimethylacetamide (5 ml) under nitrogen. (2R) Glycidyl tosylate (285 mg, 1.25 mmol) and potassium carbonate (345 mg, 2.5 mmol) were added and the reaction stirred at ambient temperature for 2.5 hours, then warmed to 40° C. and left overnight. The solvent was removed under vacuum and the residue partitioned between water and dichloromethane. The organic phase was washed with brine and dried (Na2SO4). The residue was purified by column chromatography, eluting with methylene chloride/methanol (97/3) to give 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-oxiran-2-ylmethoxy]quinazoline (339 mg, 85%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6]1C(=O)C)C.Cl.O1CCOCC1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CC(O)=O.[OH-].[Na+]>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([N:6]2[CH2:7][CH2:8][C@@H:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:5]2[C:4]([OH:3])=[O:19])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CCOC(=O)[C@@H]1[C@H](c2ccccc2)CCN1C(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2CC[C@@H](c3ccccc3)[C@H]2C(=O)O)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
N-Acetyl-cis-3-phenylproline ethyl ester (614 mg, 2.35 mmol) (prepared via the method of Chung, et al., J. Org. Chem. 55: 270-275 (1990)) was dissolved in HOAc (4 mL) and 6N HCl (12 mL) and heated at reflux for 18 hr. The mixture was cooled to room temperature and the volatiles were evaporated in vacuo to give a white solid. The solid was dissolved in 1N NaOH (15 mL) and dioxane was added (10 mL), followed by 4-toluene-sulfonyl chloride (458 mg, 2.40 mmol). The mixture was stirred at room temp for 18 hr before addition of 6N HCl to bring the pH<4. The mixture was extracted with Et2O (3×40 mL) and the extracts were dried (MgSO4), filtered, and evaporated in vacuo to give N-(toluene-4-sulfonyl)-cis-3-phenylproline as a white solid (765 mg, 94%).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]2[C:33](=[CH:34][CH:35]=1)[CH2:32][C:22]1([C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]1=[O:31])[CH2:21]2)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH2:1]([N:8]([CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:33](=[CH:34][CH:35]=1)[CH2:32][C:22]1([C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]1=[O:31])[CH2:21]2)[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)N(CC#Cc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)N(CCCc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21)Cc1ccccc1
Reaction time: 20 h

Procedure:
To a nitrogen purged solution of N-Benzyl-2,2-dimethyl-N-[3-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)prop-2-yn-1-yl]propanamide (42 mg, 0.91 mmol, Example 1) in MeOH (4 mL) was added 10% Pd/C (19 mg). The nitrogen atmosphere was exchanged for a hydrogen atmosphere using a hydrogen balloon, and then a fresh hydrogen balloon was attached. After 1 hour a mixture of alkene/alkane was observed. Allow reaction to stir for 20 hours under an atmosphere of hydrogen. The hydrogen atmosphere was then exchanged for a nitrogen atmosphere, and the mixture was filtered through celite, and washed with additional MeOH. The combined organics were concentrated in vacuo to yield a residue. The residue was then applied to a silica gel column for purification, eluting with a gradient of 1-7% MeOH in DCM to give the title compound. MS: m/z=468 (M+1). Human CGRP receptor binding Ki=45 nM. HRMS: m/z=468.2632; calculated m/z=468.2642 for C30H34N3O2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Yield: 51.3 %

Procedure:
A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.323 mmol), tert-butyl 2-amino-2-methylpropanoate hydrochloride (82 mg, 0.42 mmol), HATU (160 mmol, 0.42 mmol) and DIPEA (66 mg, 0.51 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:1, v/v) to give tert-butyl 2-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-2-methylpropanoate (75 mg, 51.8%) as a white solid. MS: (M+H)+=453; 1H NMR (300 MHz, DMSO): δ 13.93 (s, 1H), 9.13 (s, 1H), 8.57-8.52 (m, 1H), 8.48 (s, 1H), 8.30 (s, 1H), 7.72 (dd, 1H, J=9.8, 2.1 Hz), 7.21-7.15 (m, 1H), 4.18 (s, 3H), 1.63 (s, 6H), 1.25 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH:15]([CH2:17][CH3:18])[CH3:16])=[N:5][CH:4]=[C:3]1[C:19]([O:21]CC)=O.[NH3:24]>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH:15]([CH2:17][CH3:18])[CH3:16])=[N:5][CH:4]=[C:3]1[C:19]([NH2:24])=[O:21]
Reactant: N
Reactant: CCOC(=O)c1cnc(-c2ccccc2OC(C)CC)[nH]c1=O
Product: CCC(C)Oc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Yield: 87.7 %

Procedure:
A steel bomb containing ethyl (±)-1,6-dihydro-6-oxo-2-(2-sec-butoxyphenyl)pyrimidine-5-carboxylate (3.76 g.) and liquid ammonia (ca. 45 ml.) was heated on a steam bath for four hours. The ammonia was removed. A solution of the residue in ice-water was acidified with concentrated hydrochloric acid. The precipitate was recrystallized from methanol to give the title compound (2.99 g., 87.7% yield), m.p. 183°-185°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)O)c1
Yield: 86.2 %

Procedure:
The title compound was synthesized by reacting 2-amino-5-methylbenzoic acid (0.25 g, 1.65 mmol), 4-fluoro-benzenesulfonyl chloride (0.39 g, 1.98 mmol) and sodium carbonate (0.36 g, 3.39 mmol) in 3 mL of water, following the reaction procedure of 10. The white solid obtained after acidification of reaction mixture was filtered, washed with water and dried to give 12 (0.44 g, 85.42%). Crystallization with EtOH gave (0.3 g) white amorphous solid, mp: 159-160° C.; IR (CHCl3) 3177, 1662, 1342, 1148, 667 cm−1; 1H NMR (500 MHz, CDCl3) δ 2.31 (s, 3H, CH3), 7.08-7.86 (m, 7H, aromatic), 9.32 (br, 1H, NH), and 10.18 (s, 1H, COOH). HRMS calcd 332.0363 (C14H12FNO4S.Na+), found 332.0372.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([Cl:17])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[OH-].[Na+].[CH3:20][N:21]=[C:22]=[S:23].O1CCCC1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]([C:22]([NH:21][CH3:20])=[S:23])[N:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([Cl:17])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1n[nH]c(-c2ccc(Cl)c3ccccc23)n1
Reactant: CN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CNC(=S)n1nc(-c2ccc(Cl)c3ccccc23)nc1N
Yield: 5 %

Procedure:
The synthesis method of Example 7-(3) was applied. The compound (2.19 g) obtained in (4) above, a 1N sodium hydroxide solution (10.0 ml), methyl isothiocyanate (1.38 g) and tetrahydrofuran (10 ml) were used as reagents. After the reaction, silica gel column chromatography (chloroform) and recrystallization from chloroform gave 135 mg of white crystals (yield 5% from methyl 4-chloro-1-naphthoate).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.Br[C:22]1[C:23]2[CH:32]=[C:31](F)[O:30][C:24]=2[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:22]2[C:23]3[CH:32]=[CH:31][O:30][C:24]=3[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=2)=[N:3][C:4]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:5][CH:6]=1
Reactant: Cn1cc(Br)c2cc(F)oc2c1=O
Reactant: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccoc2c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A mixture of 4-chloro-5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidine (155 mg, 0.48 mmol), 4-bromo-2-fluoro-6-methylfuro[2,3-c]pyridin-7-one (120 mg, 0.44 mmol), NaHCO3 (92 mg, 1.1 mmol), Pd(dppf)Cl2 (32 mg, 10%) in dioxane/H2O (4 mL/200 uL) was bubbled with nitrogen for 7 min. The sealed vial was stirred at 70° C. for 8 h. LCMS analysis showed complete consumption of the limiting reagent. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with DCM. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (10 to 100%) in DCM to afford the title compound (151 mg, 79%) as a yellow solid. LCMS (M+H)+=434.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N+:2]=1[O-].F[B-](F)(F)F.[CH3:17][O+:18](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>ClCCl.O>[OH:18][CH2:17][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: [O-][n+]1ccc2c(c1)CCCC2
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: OCc1nccc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
5,6,7,8-Tetrahydroisoquinoline-N-oxide (12.7 g, 85 mmole) is dissolved in 250 ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen. The solution is treated with trimethyloxonium tetrafluoroborate (12.6 g, 85 mmole) and the reaction is stirred 1 h at room temperature. The volatiles are removed in vacuo to a pale oily residue. The residue is dissolved in 225 ml methanol and the solution is heated to reflux. Ammonium persulfate (8 g, 34 mmole), in 34 ml water, is added rapidly dropwise to the refluxing mixture. The reaction is stirred 30 min and is treated with a second lot of ammonium persulfate (8 g, 34 mmole) in 34 ml water. The reaction is stirred an additional hour at reflux, is cooled, and the bulk of the methanol is removed in vacuo. The residue is poured into 100 ml ice containing 100 ml 10% hydrochloric acid. The mixture is washed with 2×50 ml ethyl acetate, the pH is adjusted to 9 with 45% potassium hydroxide, and the mixture is extracted with 4×50 ml dichloromethane. The haloorganics are dried over potassium carbonate and were concentrated in vacuo to a brown solid. The crude material is chromatographed over 350 g silica gel (230-400 mesh), eluting with 3 l 20% acetone/chloroform+0.6% conc. ammonium hydroxide followed by 1 l 32% acetone/chloroform+0.6% conc. ammonium hydroxide, while collecting 50 ml fractions. Fractions 19-27 are combined and concentrated to afford 4.3 g (31%) of 1-hydroxymethyl-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[N:15]=[CH:14][C:13]=3[C:19]([CH3:23])([CH3:22])[C:20]#[N:21])[C:4]1=2>C1COCC1.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[N:15]=[CH:14][C:13]=3[C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])[C:4]1=2
Reactant: CC(C)(C#N)c1cnc(F)cc1-c1cccc2ccsc12
Agent: [Zr+4]
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(CN)c1cnc(F)cc1-c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Dissolve sodium tetrahydroborate (296 mg, 7.83 mmol) and zirconium tetrachloride (684 mg, 2.9 mmol) in THF (1 mL) to form a milky solution. Add the solution of 2-(4-benzo[b]thiophen-7-yl-6-fluoro-pyridin-3-yl)-2-methyl-propionitrile (580 mg, 1.96 mmol) in THF (20 mL) under N2 at RT. Stir the mixture at RT overnight. Quench the reaction by pouring the mixture into an ice-water solution. Extract the mixture with chloroform/IPA (3/1). Basify the aqueous phase by adding diluted ammonium hydroxide and filter. Extract the filtrate with chloroform, dry the combined organic phase, and concentrate to give a pale yellow solid (500 mg, 84%). MS (ES) m/z 301 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[N-:9]=[N+:10]=[N-:11].[Na+].O>CS(C)=O>[N:9]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1sccc1Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccsc1C=O
Temperature: 65 °C
Yield: 76.1 %

Procedure:
3-Bromothiophene-2-carbaldehyde (1) (2000 mg, 10.47 mmol) was treated with sodium azide (1994 mg, 30.7 mmol) in DMSO (27 ml). The reaction was heated to 65° C. for 48 h in a sealed 40 mL vial. The reaction mixture was then taken up into H2O (35 mL) and extracted with diethyl ether (3×20 mL). The organic product layer was washed with 25 ml of saturated NaCl solution, dried over Na2SO4, and concentrated in vacuo to give 3-azidothiophene-2-carbaldehyde (1.22 g, 76% yield).
Reaction SMILES: CC(C)CC([OH:6])C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[P:22](=[S:26])([OH:25])([OH:24])[SH:23].[O-2].[Zn+2:28]>O.C(O)(C)C>[P:22]([O-:25])([O-:24])([S-:26])=[S:23].[Zn+2:28].[P:22]([O-:25])([O-:24])([S-:26])=[S:23].[Zn+2:28].[Zn+2:28].[O-2:6].[Zn+2:28]
Reactant: CC(C)CC(C)O
Reactant: OP(O)(=S)S
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)O
Product: [O-]P([O-])(=S)[S-]
Reaction time: 4 h

Procedure:
Preparation 1. A mixture of 12 mole percent isopropanol and 88 mole percent 4-methyl-2-pentanol is reacted with phosphorus pentasulfide in approximately a 4.5:1 molar ratio at a maximum temperature of 80° C. The resulting dithiophosphoric acid mixture is reacted with a 12% molar excess of zinc oxide suspended in mineral oil at a temperature of 90° C. for four hours. After the reaction is complete, water of reaction and excess alcohols are distilled under a reduced pressure of 2.7 kPa (20 mm Hg) at 90° C. The product, containing about 9 percent by weight diluent oil, has a Total Base Number (TBN, ASTM D-2896) of 5.56 and includes about 14 percent basic zinc dithiophosphate by 31p NMR analysis. The product contains 8.70% P and 9.45% Zn. (The basic zinc salt is a known material which is formed during the zinc oxide reaction, from 3 moles of neutral zinc dithiophosphate and one mole of zinc oxide. The basic zinc salt is believed to be in the form of a tetrahedral complex that titrates with strong mineral acid, and it is believed to account for the TBN content of the product mixture.)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][N:11]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[C:13]([CH3:26])[C:12]1=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:14]=[C:13]([CH3:26])[C:12](=[O:27])[N:11]([CH3:10])[CH:16]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(Cl)nc(Cl)n2)cn(C)c1=O
Temperature: 80 °C
Yield: 55.5 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (275 mg, 1.5 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (246 mg, 1 mmol), Pd(OAc)2 (20 mg), triphenylphosphine (16 mg), and 2M Na2CO3 (1 mL, 2 mmol) in THF (6.7 mL) was purged with nitrogen for 5 min, capped, and heated to 80° C. for 3 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient (0 to 100%) EtOAc in DCM to afford the title compound (150 mg, 55%) as a white solid. LCMS (M+H)+=271.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[C:10]([CH3:11])[C:6]=2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:3]1=[O:31].C1C(=O)N([Br:39])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:39][CH2:11][C:10]1[C:6]2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:3](=[O:31])[N:2]([CH3:1])[C:7]=2[S:8][C:9]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:21])[F:22])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCn1c(=O)c2c(C)c(-c3cccc(OC(F)(F)F)c3)sc2n(C)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCn1c(=O)c2c(CBr)c(-c3cccc(OC(F)(F)F)c3)sc2n(C)c1=O
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of ethyl 3-(1,5-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (120 mg, 0.22 mmol) in CCl4 (3 mL) was added NBS (39 mg, 0.22 mmol) followed by benzoyl peroxide (5 mg). The reaction was heated at reflux for 4 h, cooled to RT and diluted with DCM (10 mL). The mixture was washed with aq. NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated to give ethyl 3-(5-(bromomethyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (100 mg, 85.7% yield) as an oil. LCMS: MH+ 535 and TR=2.087 min. Used without further purification.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH:20]=[C:6]2[CH:7]=[N:8][C:9]3[C:14](=O)[C:13]([CH3:16])=[CH:12][N:11]([CH2:17][CH2:18][CH3:19])[C:10]=3[N:5]2[CH2:4]1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:14]1[C:9]2[N:8]=[CH:7][C:6]3[N:5]([CH2:4][N:3]([O:2][CH3:1])[CH:20]=3)[C:10]=2[N:11]([CH2:17][CH2:18][CH3:19])[CH2:12][C:13]=1[CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCn1cc(C)c(=O)c2c1N1CN(OC)C=C1C=N2
Product: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16 g of 8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine-4-one and 120 ml POCl3 are mixed and heated up to reflux for 8 hours. After cooling to room temperature the reaction mixture is treated with 1200 ml crushed ice/water and stirred for 1 hour. The product is extracted with 2×300 ml dichloromethane. The collected organic layer is washed with 2×300 ml water and dried with Na2SO4. The solvent is removed under reduced pressure.