Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].CCN(CC)CC.[CH3:14][O:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24](OS(C(F)(F)F)(=O)=O)=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2cc(C#C[Si](C)(C)C)ccc12
Reaction time: 15 h

Procedure:
A solution of 15.6 ml (113 mMol) ethynyl-trimethylsilane (Fluka; Buchs/Switzerland) and 15.7 ml (113 mMol) Et3N in 250 ml degassed DMF is added to 34 g (102 mMol) 6-trifluoromethanesulfonyloxy-naphthalene-1-carboxylic acid methyl ester, 1.0 g (5.2 mMol) CuI and 5.0 g (7.1 mMol) Pd(PPh3)2Cl2 in 250 ml of degassed DMF. After 15 h at rt, the mixture is concentrated partially in vacuo at 40° C. and the residue re-dissolved in sat. NaHCO3 solution and EtOAc. The aq. phase is separated off and extracted twice with EtOAc. The organic layer is washed twice with sat. NaHCO3 solution, water/sat. NaHCO3 solution 1:1 and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/EtOAc 199:1) gives the title compound as an oil: MS: [M+1]+=283; TLC(hexane/EtOAc 19:1): Rf=0.22.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.F[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([OH:33])=[O:32])[N:26]=1.CC(C)([O-])C.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([O:22][C:25]5[N:26]=[C:27]([C:31]([OH:33])=[O:32])[CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(O)cc43)sc2C(=O)N1
Reactant: O=C(O)c1cccc(F)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(N3CCOc4ccc(Oc5cccc(C(=O)O)n5)cc43)sc2C(=O)N1
Temperature: 140 °C
Yield: 22 %

Procedure:
To a solution of Example 57 (50 mg, 0.151 mmol) in THF (4 mL) was added 2-fluoro-6-pyridinecarboxylic acid (53 mg, 0.378 mmol) and sodium tert-butoxide (73 mg, 0.755 mmol). The mixture was heated to 140° C. under microwave irradiation for 90 minutes, cooled to r.t. and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to give the title compound (15 mg, 22%) as an off-white solid. δH (CDCl3) 8.07 (1H, d, J 2.4 Hz), 7.94-7.91 (2H, m), 7.24-7.16 (1H, m), 7.00 (1H, d, J 8.9 Hz), 6.85 (1H, dd, J 8.9 and 2.6 Hz), 5.45 (1H, s), 4.52-4.20 (2H, m), 4.20-4.01 (2H, m), 2.84 (2H, s), 1.38 (6H, s). LCMS (ES+) 453.0 (M+H)+, RT 2.94 minutes (Method 1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22]>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:22][C:21]1[CH:23]=[CH:24][C:25]([F:26])=[C:19]([Cl:18])[CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OC(C)=O
Temperature: 88 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (2.52 g), 3-chloro-4-fluoroaniline (1.49 g) and isopropanol (60 mL) was stirred at 88° C. for 5 h. The reaction mixture was cooled to room temperature, filtered to afford the desired compound as a solid (2.51 g, 81.00%).
Reaction SMILES: C(O)(=O)C.[Cl-].[NH4+:6].C[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:15]=[C:16]([C:17](=[NH:19])[O-])[C:9]=12>CO>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:14]1[C:10]2=[N:11][CH:12]=[CH:13][CH:8]=[C:9]2[C:16]([C:17]([NH2:19])=[NH:6])=[N:15]1
Reactant: [NH4+]
Reactant: Cc1ccnc2c1c(C(=N)[O-])nn2Cc1ccccc1F
Agent: [Cl-]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12

Procedure:
33.76 g (32.19 ml, 562 mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium chloride are added to the solution of methyl(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidate in methanol obtained from example 2E), and the mixture is stirred under reflux overnight. The solvent is evaporated in vacuo, the residue is thoroughly triturated with acetone, and the precipitated solid is filtered off with suction.
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[F:21][CH2:22][CH2:23][N:24]([C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:7]([N:34]2[CH2:35][CH2:36][C@H:32]([N:24]([CH2:23][CH2:22][F:21])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:33]2)[C:8]([F:9])([F:10])[F:11])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N(CCF)[C@H]1CCNC1
Reactant: O=S(=O)(O[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCF)[C@H]1CCN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 48.3 %

Procedure:
To a suspension of 5% Pd/C (1.4 g, 2.2 mmol) in ethanol (12 mL) was added slowly a solution of (S)-benzyl 3-(tert-butoxycarbonyl(2-fluoroethyl)amino)pyrrolidine-1-carboxylate (2.44 g, 21.6 mmol) in methanol (5 mL). The mixture was evacuated and backfilled with nitrogen and then evacuated and backfilled with hydrogen, then stirred under a hydrogen atmosphere for 2 hours. The suspension was filtered through a pad of Celite and washed with a methanol (50 ml). The filtrate was concentrated under reduced pressure to afford (S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate. To a solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (0.97 g, 2.82 mmol) in anhydrous THF (5 mL) was added (S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate (0.92 g, 3.95 mmol) and K2CO3 (0.59 g, 4.23 mmol). The resulting mixture was heated with stirring at 50° C. for 18 hours. After cooling to ambient temperature the mixture was partitioned between water (12 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure and the residue obtained purified by column chromatography (Biotage 25M; 10% ethyl acetate:hexanes) to afford tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl(2-fluoroethyl)carbamate (0.58 g, 48%).
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][C@@H:3]1[O:4]C.F[C@@H]1[C@H](O)[C@@H](CO)O[C@H:14]1[O:15]C>>[F:1][C@@H:2]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][CH:3]([OH:4])[C@@H:14]1[OH:15]
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Product: OC[C@H]1OC(O)[C@H](O)[C@H](F)[C@@H]1O
Yield: 99 %

Procedure:
The mixture of compounds (4) and (5) obtained in item (2) above (10.0 g) was dissolved in pyridine (200 ml), to which benzoyl chloride (17.5 ml) was then added, and the resulting mixture was allowed to stand at room temperature for 30 minutes. After addition of a small amount of water, the resultant reaction solution was concentrated, and the syrup obtained was extracted with chloroform. The solution in chloroform was washed with a 5% aqueous potassium hydrogen sulfate solution, a 5% aqueous sodium hydrogen carbonate solution and water, successively, and then dried over anhydrous sodium sulfate and concentrated to afford a mixture of the titled compounds (6) and (7) (22.3 g) as colorless crystals. Yield: 99%.
Reaction SMILES: C([O:4][CH:5]([CH3:25])[CH2:6][C:7]1[CH:20]=[C:19]([CH3:21])[C:18]2[C:17](=[O:22])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:23])[C:9]=2[C:8]=1[CH3:24])(=O)C>C([O-])([O-])=O.[K+].[K+].CO>[CH3:24][C:8]1[C:9]2[C:10](=[O:23])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17](=[O:22])[C:18]=2[C:19]([CH3:21])=[CH:20][C:7]=1[CH2:6][CH:5]([OH:4])[CH3:25]
Reactant: CC(=O)OC(C)Cc1cc(C)c2c(c1C)C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(CC(C)O)c(C)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The acetoxy compound (Compound 1.2) (4 mg, 14 μmole) was dissolved in 4 mL of a solution of 5% K2CO3 and methanol (1 to 1 ratio). After 6 hours of stirring at room temperature, the reaction mixture was evaporated to half of the original volume for CHCl3 -H2O extraction. Then, the organic layer was dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. Purification by flash silica column chromatography yielded the hydroxy compound (Compound 1.3) in quantitative yield. 1H NMR (300 MHz, CDCl3) δ 8.04 (2H, m), 7.55 (2H, m), 7.31 (1H, s), 4.45 (1H, t), 3.42(2H, m), 2.95 (2H, t), 2.69 (6H, s), 1.64 (2H, m).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH:8]([CH3:36])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[C:14]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:27][N:18]([C:15]1[C:14]([C:28]#[C:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:13][C:12]([NH:11][C:9](=[O:10])[CH:8]([NH:7][CH3:6])[CH3:36])=[CH:17][CH:16]=1)[C:19]([CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:20]
Reactant: CC(C(=O)Nc1ccc(N(C)C(=O)C2CCOCC2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C(=O)Nc1ccc(N(C)C(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
A mixture of tert-butyl-N-methyl-N-[1-[[5-[methyl(oxane-4-carbonyl)amino]-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate F5b (5 mg) and DCM:TFA (9:1, 1 ml) is stirred at RT for 100 minutes. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 7 mg. HPLC-MS: M+H=421; tR=1.33 min (*Method—1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH2:21]([NH2:23])[CH3:22]>CN(C)C=O.O>[Cl:8][C:7]1[C:2]([NH:23][CH2:21][CH3:22])=[N:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1
Reactant: CCN
Reactant: Clc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Reaction time: 6 h

Procedure:
2,3-Dichloro-5,6-diphenylpyrazine (2.00 g, 0.0066 moles), is suspended in dimethylformamide (DMF) (12 ml) and treated with a solution of ethylamine (70% in water) (3.5 ml) in DMF (6 ml) and the mixture is warmed at 40°-45° C for 30 minutes then allowed to stand at room temperature for 6 hours. The solution is diluted with water (80 ml) and after standing overnight the solid is filtered off, washed with water and dissolved in hot ethyl alcohol, filtered, concentrated and cooled to yield 1.19 g of greenish-yellow solid. m.p. 115°-122°. This material is recrystallized from an ethyl alcohol-hexane mixture, yield 0.84 g, m.p. 121°-125°. Identity of the product is confirmed by infrared, nuclear magnetic resonance and mass spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH3:10])=O)=[CH:4][C:3]=1[S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.B>C1COCC1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH3:10])=[CH:4][C:3]=1[S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H](NC(=O)c1ccc(Cl)c(Sc2ccccc2)c1)c1cccc(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(Sc2ccccc2)c1)c1cccc(Cl)c1
Yield: 44.9 %

Procedure:
To a solution of (R)-4-chloro-N-(1-(3-chlorophenyl)ethyl)-3-(phenylthio)benzamide 33 (0.631 g, 1.57 mmol) in THF (8 mL) was added borane (0.110 g, 7.95 mmol) (8 mL, 1 M in THF). The reaction mixture was heated to reflux for 2 d, quenched with 1 M NaOH, and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 50% EtOAc in hexanes) gave (R)—N-(4-chloro-3-(phenylthio)benzyl)-1-(3-chlorophenyl)ethanamine 34 (0.274 g, 45.0% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.26 (d, J=6.5 Hz, 3H), 3.41 (d, J=13.7 Hz, 1H), 3.50 (d, J=13.7 Hz, 1H), 3.65 (q, J=6.7 Hz, 3H), 6.93 (s, 1H), 7.05-7.09 (m, 2H), 7.20-7.25 (m, 2H), 7.37-7.43 (m, 6H). Mass spectrum: calculated for C15H14Cl2NS 387.1. found 388.1 (M++1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C@:14]3([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][N:17]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]>C(O)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([C@:14]3([CH2:29][C:30]([OH:32])=[O:31])[S:20](=[O:21])(=[O:22])[CH2:19][CH2:18][N:17]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCCS(=O)(=O)N1CC[C@](CC(=O)OC(C)(C)C)(c2ccc(-c3ccc(CC)cc3)s2)S(=O)(=O)CC1
Solvent: O=CO
Product: CCCS(=O)(=O)N1CC[C@](CC(=O)O)(c2ccc(-c3ccc(CC)cc3)s2)S(=O)(=O)CC1
Yield: 108.9 %

Procedure:
A solution of tert-butyl 2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-propanesulfonyl-1,4-thiazepin-7-yl]acetate (4.70 g) in formic acid (50 ml) was stirred for 2 hours at room temperature. The volatile was removed in vacuo and three evaporation from chloroform (30 ml) afforded 2-[((S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-propanesulfonyl-1,4-thiazepin-7-yl]acetic acid (4.60 g) as a pale yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([S:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[CH2:2]1.[OH2:17].OOS([O-])=O.[K+].C[OH:25]>>[O:1]1[CH2:5][CH2:4][CH:3]([S:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=2)(=[O:25])=[O:17])[CH2:2]1
Reactant: O
Reactant: COC(=O)c1ccc(SC2CCOC2)cc1
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Product: COC(=O)c1ccc(S(=O)(=O)C2CCOC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
Methyl 4-tetrahydrofuran-3-ylsulfanylbenzoate (1.01 g, 4.24 mmol) was dissolved in methanol (25 mL), followed by the addition of water (2.5 mL), and Oxone (2.61 g, 4.24 mmol). The reaction mixture was stirred at room temperature for 24 hours. An additional 0.1 eq of Oxone (0.26 g) was added and the reaction mixture was stirred for 2 hours, then filtered and the solvent was concentrated in vacuo. The resulting residue was dissolved in dichloromethane (30 mL) and washed with water (2×25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield methyl 4-tetrahydrofuran-3-ylsulfonylbenzoate (1.07 g, 93%) as a yellow solid. ESI-MS m/z calc. 270.1. Found 271.3 (M+1)+; Retention time: 1.02 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:10][CH2:11][CH:12]=O)=[CH:7][C:8]#[N:9])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[NH:10][CH:11]=[CH:12][C:7]=2[C:8]#[N:9])=[CH:4][CH:3]=1
Reactant: N#CC=C(NCC=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 108 mL of trifluoroacetic acid stirred at 23° C. is added 54.00 g (0.183 mol) of solid p-chloro-β-[(formylmethyl)amino]cinnamonitrile, diethyl acetal over a period of 45 minutes. This addition produced an exotherm to 38° C. and, 32 minutes into the addition, a solid started to precipitate. After stirring at room temperature for 30 minutes, the reaction mixture is vacuum filtered and the collected solid is washed first with trifluoroacetic acid, secondly with an ethyl acetate-hexane mixture, and finally with hexane. The yield is 16.83 g (45.4%) of an off-white solid, mp 165°-166° C.
Reaction SMILES: Br[C@H:2]([C@H:5]1[CH2:7][O:6]1)[CH2:3][CH3:4].[CH:8]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:15]1([CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:21]2[CH2:7][C@H:5]([OH:6])[C@@H:2]2[CH2:3][CH3:4])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC[C@H](Br)[C@H]1CO1
Product: CC[C@H]1[C@@H](O)CN1C(c1ccccc1)c1ccccc1
Yield: 28.8 %

Procedure:
The same operation as in Example (234b) was performed using (2R*)-2-[(1S*)-1-bromopropyl]oxirane obtained in Example (235a) (1.50 g, 9.09 mmol) and benzhydrylamine (1.57 mL, 9.09 mmol), to obtain 699 mg of the title compound as a pale yellow solid (29%).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH2:19][CH2:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2cccc3cc[nH]c23)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2cccc3c2NCC3)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a solution of 310 mg (0.76 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-phenethyl-amide in 5 ml acetic acid cooled to 0° C. were added in portions 142 mg (2.26 mmol) of sodium cyano borohydride. The reaction mixture was stirred for 2 h at 0° C. and 2N aqueous sodium hydroxide solution was added until the reaction mixture was basic. The reaction mixture was extracted with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated to yield 310 mg (100%) of product as a colorless oil. MS (ISP) 413.5 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].CN[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:37][N:38](C)C=O>>[CH:23]1([CH2:37][NH:38][CH2:2][C:3]([NH:5][C:6]2[CH:19]=[CH:18][C:17]3[NH:16][C:15](=[O:20])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]=3[CH:7]=2)=[O:4])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CNC1CCCCC1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: CN(C)C=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: O=C(CNCC1CCCCC1)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared from the compound of Example 2 and N-methylcyclohexylamine. To a solution of 2-chloro-N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-acetamide (45 mg) in N,N-dimethylformamide (10 mL) was added potassium phosphate (68 mg) and N-methylcyclohexylamine (0.025 mL). The solution stirred at room temperature for 5 hours followed by evaporation of the solvent. The light brown product was washed with water and filtered (30 mg). 1H-NMR (300 MHz, DMSO-d6), 11.69 (br s, 1H), 9.76 (br s, 1H), 8.65 (s, 1H), 8.34 (t, 2H), 7.87 (m, 2H), 7.66 (t, 1H), 7.32 (t, 1H), 3.18 (s, 2H), 2.34 (s, 3H), 1.80 (m, 4H), 1.60 (m, 2H), 1.23 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:32]=[CH:31][C:22]([O:23][CH2:24][CH2:25]OS(C)(=O)=O)=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:33](CN)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH2:42]([N:44](CC)CC)C>CC(N(C)C)=O>[CH2:33]([N:44]([CH3:42])[CH2:25][CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16]2[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:14]3[N:15]=2)=[CH:32][CH:31]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(-c2cccc3nc(Nc4ccc(OCCOS(C)(=O)=O)cc4)nn23)cc1
Reactant: NCCc1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cccc3nc(Nc4ccc(OCCN(C)Cc5ccccc5)cc4)nn23)cc1
Temperature: 130 °C

Procedure:
Methanesulfonic acid 2-{4-[5-(4-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenoxy}-ethyl ester (0.05 g, 0.11 mmol) was dissolved in dimethylacetamide (1 mL). N-Benzylmethylamine (0.071 mL, 0.55 mmol) and triethylamine (0.076 mL, 0.55 mmol) were added and the reaction was heated to 130° C. for 15 minutes in the microwave. The reaction mixture was transferred to a vial and purified by preparatory HPLC. LCMS method: 2, RT: 2.86 min, MI: 466 [M+1].
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:2].C1(N=[CH:15][C:16]2[O:17][CH:18]=[CH:19][C:20]=2[CH3:21])C=CC=CC=1.ClC(OCC)=O>C1(C)C(C)=CC=CC=1>[CH2:6]([O:5][C:3]([C:1]1[CH:21]=[C:20]2[CH:19]=[CH:18][O:17][C:16]2=[CH:15][N:2]=1)=[O:4])[CH3:7]
Reactant: Cc1ccoc1C=Nc1ccccc1
Reactant: CCOC(=O)C#N
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2ccoc2cn1
Temperature: 130 °C
Yield: 52.2 %

Procedure:
Ethyl cyanoformate(21.4 g, 0.216 mol) and 3-methylfuran-2-carbaldehyde-N-phenylimine(10.0 g, 54.1 mmol) were mixed at room temperature in xylene (50 mL) then heated to reflux at 120 to 140° C. with stirring. A xylene (30 mL) solution of 11.7 g (0.108 mol) of ethyl chloroformate was added dropwise for an hour to the resulting mixture. After all the solution had been added, the reaction mixture was heated to reflux for 2 hours, it was allowed to cool to room temperature, and the solvent was distilled off to give 14.0 g of crude product. This product was purified by column chromatography on silica gel, giving 5.40 g (52.3% yield) of 5-ethoxycarbonylfuro[2,3-c]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][Si](C)(C)C)[O:8][CH2:7][CH2:6][C:5]2(O[Si](C)(C)C)[C:17]#N.[OH2:24].[OH2:25].[Sn](Cl)Cl.Cl.C(OC(C)C)(=O)C>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:17]([OH:25])=[O:24]
Reactant: C[Si](C)(C)Oc1cc2c(cc1Cl)C(C#N)(O[Si](C)(C)C)CCO2
Reactant: O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)O
Product: O=C(O)C1CCOc2cc(O)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 125.2 %

Procedure:
A 20-liter 4-neck round-bottom flask was charged with glacial acetic acid (2.04 L), 6-chloro-4,7-bis(trimethylsilyloxy)chroman-4-carbonitrile (2.2 kg, 5.94 mol), and tin(II) chloride dihydrate (3.35 kg, 14.85 mol) and the resulting mixture was stirred at ambient temperature. Concentrated hydrochloric acid (5.0 L, 60 mol) was added, and the resulting mixture was stirred and heated to 80-85° C. for 12 hours. The reaction mixture was cooled to ambient temperature and water (3.6 L) was added, and stirring was continued at ambient temperature for 15 minutes. Isopropyl acetate (11.5 L) and water (5.8 L) were added, and stirring was continued at ambient temperature for 15 minutes. The layers were separated, and the aqueous layer was extracted with isopropyl acetate (2×2 L). The organic layers were combined and washed with brine (3×6 L), then dried over sodium sulfate and concentrated under reduced pressure at a temperature below 50° C. to afford crude 6-chloro-7-hydroxychroman-4-carboxylic acid as a brown semi-solid (1.70 kg, 125% yield).