Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[BrH:13]>CO.OO>[Br:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([Cl:1])=[C:3]([OH:12])[CH:4]=[CH:5]2
Reactant: Oc1ccc2ccccc2c1Cl
Reactant: Br
Agent: OO
Solvent: CO
Product: Oc1ccc2cc(Br)ccc2c1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 400 mg (2.24 mmol) of 1-chloronaphthalen-2-ol in 3 mL of MeOH, HBr (purum p.a., ≧62%, 270 μL) and H2O2 (50 wt. % in water solution, 27 μL) were added. The resulting mixture was heated at 40° C. and stirred overnight. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 6-bromo-1-chloronaphthalen-2-ol as pale yellow solid which was used in the next step without further purification. HPLC-MS (ESI+): m/z 258.51 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([NH:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Yield: 78.8 %

Procedure:
A mixture of 2-chloro-5-nitro-pyridine (3.4 g, 0.021 mol), (S)-(−)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (4 g, 0.021 mol), and potassium carbonate (14.5 g, 0.105 mol) in acetonitrile (50 mL) was heated at reflux for 24 h. The reaction was monitored by LCMS and additional (S)-(−)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester was added until the reaction was driven to completion. The reaction mixture was then filtered and concentrated to give (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.1 g, 78.6%) as a yellow solid. LCMS calcd for C14H20N4O4 (m/e) 308, obsd 307.1 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@H:10]2[N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[O:18][CH3:19].[OH-].[K+].S(=O)(=O)(O)O>C(O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]2[N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
10.0 g of (±)-trans-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene (compound I1) and 20.0 g of potassium hydroxide are dissolved in 150 ml of ethanol and 35 ml of dimethylformamide. A solution of 17.5 ml of conc. sulfuric acid in 60 ml of ethanol is then added dropwise such that the internal temperature does not exceed 4° C. After stirring for 1 h, the mixture is added to 1 l of ice water, the precipitate is filtered off with suction, washed with water and dried, and the crude product is recrystallized in ethanol. 8.6 g of the title compound of m.p. 82.5-84° C. are obtained.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])C.[NH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([NH:17][C:11]2[CH:10]=[C:9]3[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:7]=[CH:8]3)=[CH:13][CH:12]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: CCOC(=O)c1ncc2cc(NC(=O)c3ccc(F)cc3)ccc2c1O
Product: O=C(O)CCNC(=O)c1ncc2cc(NC(=O)c3ccc(F)cc3)ccc2c1O

Procedure:
3-{[7-(4-Fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid was prepared from 7-(4-Fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(b) using beta-alanine. MS ESI(−) m/e: 395.9953 (M−1).
Reaction SMILES: [CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:8])[CH3:2].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([O:19][CH3:20])[CH:12]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][N:5]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([O:19][CH3:20])[CH:12]=2)[C@H:4]1[CH3:8])[CH3:2]
Reactant: CC[C@]1(O)CCN[C@H]1C
Reactant: COc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(OC)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-methylpyrrolidin-3-ol 0.5 oxalate (257 mg), 4-fluoro-2-methoxybenzonitrile (447 mg) and lithium carbonate (218 mg), the title compound was obtained as colorless oil (yield: 305 mg, yield: 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>CCO>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: NC=O
Solvent: CCO
Product: O=c1[nH]cnc2ccc(Br)cc12
Temperature: 70 °C
Yield: 81 %

Procedure:
Briefly, 2-amino-5-bromobenzoic acid (A, 50.0 g, 0.233 mmol, 1.0 equiv) is added to formamide (50.0 mL, d=1.133, 56.7 g, 1.26 mmol). The reaction mixture is heated at reflux for 12 h. The solution is then cooled to 70° C., and EtOH (100 mL) is added to the reaction mixture. The resultant precipitates are collected by filtration, washed with EtOH (50 mL), and dried under vacuum to provide the desired 6-bromo-3H-quinazolin-4-one (B, 42.5 g, 0.189 mol) in 81% yield: ESI-MS m/z 225.0 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH:3]([N:6]1[CH2:13][CH:12]2[C:14](=O)[CH:8]([CH2:9][S:10][CH2:11]2)[CH2:7]1)([CH3:5])[CH3:4].NN.C1C2C(=CC=CC=2)CCC1.C>C(O)COCCOCCO.O.C(O)(C)C.CCO>[CH:3]([N:6]1[CH2:13][CH:12]2[CH2:14][CH:8]([CH2:9][S:10][CH2:11]2)[CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CC2CSCC(C1)C2=O
Agent: C
Agent: NN
Agent: [K+]
Solvent: OCCOCCOCCO
Solvent: O
Solvent: CCO
Product: CC(C)N1CC2CSCC(C2)C1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a mixture of KOH pellets (85%, 3.96 g, 60 mmol) and the ketone (26, 1.0 g, 5 mmol) in triethylene glycol (25 mL) was added hydrazine (95%, 1.69 g, 50 mmol) in one portion in a 70 mL, jacketed flask equipped with a magnetic stirrer, a heating mantle, a standard condenser, a lower take-off condenser with a N2 inlet, and two glass stoppers. A heating temperature of 200°-210° C. for 5 h was produced by boiling tetralin (bp 207° C.) in the jacket. After cooling to RT, the solution was diluted with chilled water (100 mL) and extracted with ether (4×50 mL). Combined extracts were washed with 10% NaOH (50 mL) and saturated NaCl (50 mL), dried (Na2SO4, overnight), filtered, and concentrated to a yellow oil (0.8 g). Dissolution of the oil in ether (50 mL) via magnetic stirring and cooling (5° C.) with an external ice bath was followed by dropwise addition of a solution of HClO4 (60%, 1.08 g, 6.45 mmol) in isopropyl alcohol (3 mL) over 10 min. Stirring of the mixture an additional 10 min, filtering the precipitated salt, and then washing the latter with ether (~50 mL) gave an off-white solid. Dissolving the salt in hot 95% EtOH and decolorizing the solution with Norit, followed by filtering, and cooling, afforded 0.91 g (63.6%) of salt (8) as a white solid; mp 281°-282.5° C. IR (KBr) cm-1 3060 (N--H), 3000, 2960, 2935 (C--H), 1090 (Cl--O); 1H NMR (DMSO-d6) δ1.28 (d, 6H, CH3), 1.76 [d, 1H, H(9), J=13.3 Hz], 1.91 [d, 1H, H(9), J=12.9 Hz], 2.35 [bs, 2H, H(1,5)], 2.78 [bd, 2H, H(2,4)ax, J=12.2 Hz], 3.14 [bd, 2H, H(2,4)eq, J=13.6 Hz], 3.29-3.57 [m, 3H, H(6,8)ax and CH(CH3)2 ], 3.62 [d, 2H, H(6,8)eq, J=12.7 Hz], 9.07 (bs, 1H, N--H); 13C NMR (DMSO-d6) ppm 16.19 (q, CH3), 25.51 [d, C(1,5)], 28.35 [t, C(9)], 30.69 [t, C(2,4)], 52.36 [t, C(6,8)], 58.66 [d, CH(CH3)2 ]; 15N NMR (DMSO-d6) ppm 58.47 [N(7)]. Anal. Calcd. for C10H20ClNO4S: C, 42.03; H, 7.05. Found: C, 42.10; H, 7.18.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:4]([C:19]([F:22])([F:20])[F:21])[N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccncc2)c(C(F)(F)F)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(C(F)(F)F)c(-c2ccncc2)cc1C(=O)O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of the product of part (c), 10% aqueous sodium hydroxide (75 ml) and 125 ml methanol was stirred at 100° C. for 6 hours. The reaction mixture was concentrated in vacuo and the residue neutralized with dilute acetic acid to pH 4-5. The solid product was collected, washed with water and dried to give 12.08 g of 2-amino-5-(4-pyridinyl)-6-trifluormethyl-3-pyridinecarboxylic acid as a colorless solid, m.p. above 283° C.(decompn.).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)[CH3:10].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+].C(#N)CC.O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:9]([O:11][CH2:12][C@H:13]2[CH2:15][O:14]2)[CH3:10])[C:2]=1/[CH:18]=[CH:17]/[C:16]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cc1cccc([C@@H](C)OC[C@H]2CO2)c1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: O
Product: CCOC(=O)/C=C/c1c(C)cccc1[C@@H](C)OC[C@H]1CO1
Temperature: 25 °C
Yield: 63 %

Procedure:
(2R)-2-{[(1R)-1-(2-Bromo-3-methylphenyl)ethoxy]methyl}oxirane (1505 mg, 5.57 mmol), which had been obtained in Example 3 (3b), ethyl prop-2-enoate (910 μL, 8.36 mmol), palladium acetate (II) (126 mg, 0.56 mmol), tris(2-methylphenyl)phosphine (170 mg, 0.56 mmol), and potassium carbonate (1537 mg, 11.1 mmol) were suspended in a mixed solvent (27.5 mL) of propionitrile-water (2:1), and stirred with heating under reflux for 5 hours. The reaction solution was cooled to room temperature, filtered by using Millicup-LH, and washed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After that, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a pale yellow oily substance (1025 mg, yield 63%).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[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:26])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[C:17]([CH3:25])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Agent: Cl
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(C)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.5) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Light brown solid. MS (ISP) 525.2 [(M+H)+]; mp 261° C.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11](=O)[NH:10][C:9]=3[N:4]2[N:3]=1.C(Cl)(Cl)[Cl:23].O=S(Cl)Cl.CN(C=O)C>CCCCCCC.CCOC(C)=O>[Cl:23][C:11]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:13][C:8]2[CH:7]=[N:6][C:5]3[N:4]([N:3]=[C:2]([CH3:1])[CH:21]=3)[C:9]=2[N:10]=1
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: Cc1cc2ncc3cc(-c4ccccc4)c(Cl)nc3n2n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a 250 mL round bottom flask was added 2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-8(9H)-one (1-3) (3 g, 10.9 mmol, 1 eq.), CHCl3 (120 mL), SOCl2 (5.17 g, 3.17 mL, 43.5 mmol, 4 eq.) and DMF (158.9 mg, 168.3 uL, 2.17 mmol, 0.2 eq.). The mixture was heated to 70° C. in an oil bath for 1 h. After 1 h, additional SOCl2 (1.6 mL, 21.8 mmol, 2 eq.) and DMF (168.3 uL, 2.17 mmol, 0.2 eq.) were added. The mixture was maintained at 70° C. for an additional 2 h. After 3 h total, LCMS analysis and TLC analysis (heptane:EtOAc (3:7)) of the resulting light brown solution indicated that the reaction was complete. The reaction was concentrated in vacuo and the residue diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 solution (50 mL), and the aqueous phases re-extracted with EtOAc (3×200 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated to give 3.2 g of material which was purified by silica gel chromatography using EtOAc/heptane as the eluent to give 8-chloro-2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine (1-4) as an yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH2:24])[CH2:12][CH2:11]2)=[N:2]1.[CH3:25][C:26]([CH3:28])=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH:26]([CH3:28])[CH3:25])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.4 %

Procedure:
A round bottomed flask was charged with 4.9 g (0.015 mol) 2-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine, 50 mL ClCH2CH2Cl, 1.2 mL (0.016 mol) acetone, 0.93 mL (0.016 mol) HOAc, and 5.2 g (0.024 mol) NaBH(OAc)3. After stirring for 15 h at rt the reaction was quenched with 50 mL 2M K2CO3. The organic layer was separated, dried and concentrated in vacuo to give 5.5 g (100% yield) of the desired material as a yellow-orange oil. MS (APCI): 381 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.47–7.42 (m, 1H), 7.35–7.31 (m, 1H), 7.03–7.00 (m, 2H), 6.54–6.50 (m, 2H), 3.61–3.55 (m, 5H), 2.75–2.71 (m, 6H), 2.65–2.60 (m, 2H), 1.18 (d, J=6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1
Reactant: C[O-]
Reactant: Nc1cncc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1cncc(N)n1
Temperature: 130 °C
Yield: 79.7 %

Procedure:
A mixture of 6-chloro-2-pyrazinamine (200 mg, 1.544 mmol) and sodium methoxide (250 mg, 4.63 mmol) in methanol (3.9 ml) was heated to 130° C. via a microwave reactor for 60 min. The crude product mixture was purified by RP-HPLC to give 6-(methyloxy)-2-pyrazinamine (154 mg, 1.231 mmol, 80% yield). MS (ES+) m/z 125.8 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH:14][C:23](=[O:25])[CH3:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CC1(c2cccc(Br)c2)CCSC(N)=N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1=NC(C)(c2cccc(Br)c2)CCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a 0° C. solution of 4-(3-bromo-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine (10 g, 35 mmoles, 1 equiv) and triethylamine (4.3 g, 42 mmoles, 1.2 equiv) in dichloromethane (70 mL) is added dropwise acetyl chloride (2.8 g, 35 mmoles, 1 equiv) over 5 minutes. The reaction is allowed to warm to ambient temperature. After 1 h, the reaction is diluted with dichloromethane and extracted with water. The organic layers are separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography eluting with hexane:ethyl acetate (1:1) to give the title compound (87% yield): MS (m/z): 327, 329 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1.[CH:10](=O)[CH3:11].C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.C(O)(=O)C>[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([NH:1][CH2:10][CH3:11])[CH:3]=1)#[N:9]
Reactant: N#Cc1cncc(N)c1
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNc1cncc(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a solution of 5-amino-3-cyanopyridine (300 mg, 2.52 mmol) in methanol (10 ml) was added acetaldehyde (1.42 ml, 25.1 mmol), and the mixture was stirred at room temperature for 10 minutes. Next, sodium cyanoborohydride (950 mg, 15.1 mmol) was added, and acetic acid was further added to adjust the pH of thereaction mixture to about 6. The mixture was stirred for 5 hours. After the reaction was completed, the reaction mixture was neutralized with an aqueous sodium carbonate solution and extracted with diethyl ether (30 ml×3). The diethyl ether layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (Wako Gel C-200, 20 g; eluted with chloroform:methanol=200:1) to give 3-cyano-5-ethylaminopyridine (200 mg, 1.36 mmol, yield 54%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10])[N:3]=[N:2]1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([CH3:30])[CH:26]=[C:27]([CH3:29])[CH:28]=3)=[O:20])[CH2:17][CH2:18]2)=[O:10])[N:3]=[N:2]1
Reactant: Cc1cc(C)cc(COC(=O)N2CCC(N)CC2)c1
Reactant: O=C(Cl)CCCc1c[nH]nn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(COC(=O)N2CCC(NC(=O)CCCc3c[nH]nn3)CC2)c1
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(1H-1,2,3-triazol-4-yl)butanoic acid chloride in DCM (5 ml) at RT (168 mg, 0.967 mmol) was added 3,5-dimethylbenzyl 4-aminopiperidine-1-carboxylate (318 mg, 1.064 mmol) and Huenig's Base (0.338 mL, 1.934 mmol) and the reaction mixture was allowed to stir for 3 hrs. The reaction mixture was diluted with DCM and washed with a saturated solution of brine. The layers were separated and the organic portion dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM as eluent to afford the title product;
Reaction SMILES: C(OC(=O)[N:7]([CH3:24])[C:8]1[C:13]([CH3:14])=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=1)(C)(C)C.Cl[C:27]1[N:28]=[C:29]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:42][CH2:41][N:40]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:39][CH2:38]3)[S:33][C:31]=2[N:32]=1>>[CH3:24][NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:27]2[N:28]=[C:29]([N:47]3[CH2:48][CH2:49][O:50][CH2:51][CH2:52]3)[C:30]3[CH:35]=[C:34]([CH2:36][N:37]4[CH2:38][CH2:39][N:40]([S:43]([CH3:46])(=[O:44])=[O:45])[CH2:41][CH2:42]4)[S:33][C:31]=3[N:32]=2)=[CH:10][N:9]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N(C)C(=O)OC(C)(C)C
Product: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cc1C

Procedure:
Methyl-[3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester was reacted with 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine in General Procedure A. Purification on silica yielded 361. NMR: (CDCl3): 2.54-2.58 (4 H, m), 2.72 (3 H, s), 3.04-3.07 (3 H, m), 3.18-3.21 (4 H, m), 3.72 (2 H, s), 3.78-3.80 (4 H, m), 3.85-3.88 (4 H, m), 4.40 (1 H, s, NH), 7.031 (1 H, s, Ar), 8.16 (1 H, s, Ar) and 9.09 (1 H, s, Ar). MS: (ESI+): MH+=518.24
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:26])[N:13](CC3C=CC(OC)=CC=3)[C:12](=[O:23])[C:11]([CH3:25])([CH3:24])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:26])[NH:13][C:12](=[O:23])[C:11]([CH3:25])([CH3:24])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)C(C)(C)OC[C@@]2(C)c2cccc(Br)c2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1(C)OC[C@@](C)(c2cccc(Br)c2)NC1=O
Temperature: 73 °C

Procedure:
A solution of (R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,2,5-trimethyl-morpholin-3-one (487 mg, 1.2 mmol) and anisole (2.305 g, 21.3 mmol) in trifluoroacetic acid (6 ml) was treated dropwise with trifluoromethanesulfonic acid (1.19 ml). After complete addition, the violet reaction mixture was heated at 73° C. for 23 hours. The cooled reaction mixture was poured into a saturated solution of sodium hydrogen-carbonate which was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 66/34 as the eluent. The product containing fractions (550 mg, orange foam) were collected and engaged in the next step without further purification and characterization.
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][C@H:8]1[C@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]1([Cl:18])[Cl:17])(=O)C.O1CCCC1.Cl>CO.O>[Cl:17][C:9]1([Cl:18])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:8]1[CH2:7][OH:6]
Reactant: CC(=O)OC[C@H]1[C@H](c2ccccc2)C1(Cl)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@H]1[C@H](c2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of KOH (3.36 g, 60 mmol) and the product of Step 1, above, (10.36 g, 40 mmol) in a mixture of methanol (30 ml), tetrahydrofuran (30 ml) and water (90 ml) was stirred for 3 hours at room temperature. The reaction mixture was neutralized with 1N aqueous hydrochloric acid and extracted with diethyl ether (100 ml+2×50 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2×50 ml) and brine (50 ml), then dried over MgSO4. Evaporation of the solvent afforded (2,2-dichloro-trans-3-phenylcyclopropyl)methanol in quantitative yield. To a stirred solution of the alcohol thus prepared (4.34 g, 20 mmol), N,O-di-tert-butoxycarbonylhydroxylamine (5.83 g, 25 mmol), and triphenylphosphine (6.56 g, 25 mmol) in toluene (40 ml), cooled to −42° C. was added dropwise a solution of diethyl azodicarboxylate (4.35 g, 25 mmol) in toluene (5 ml) over 15 minutes under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature overnight, insolubles were removed by filtration and the filtrate concentrated under reduced pressure. The resultant residue was purified by column chromatography (SiO2, 300 g; 8% ethyl acetate in n-hexane) affording the title compound (8.09 g, 94% yield).