Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.O1CCCC1.[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27]>[OH-].[K+].C(O)C>[C:10]([C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=1)([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH2:27][CH2:26][C:25]([O:29][CH2:30][CH3:31])=[O:28])#[N:11]
Reactant: C=CC(=O)OCC
Reactant: N#CC(c1cccc(C(F)(F)F)c1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C#N)(c1cccc(C(F)(F)F)c1)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of 5.0 g. of α-[3-(trifluoromethyl)phenyl]-4-morpholineacetonitrile in 200 ml. of tetrahydrofuran stirred at room temperature is added 30 drops of 30% potassium hydroxide in ethanol. To the mixture is added 10 ml. of ethyl acrylate. After one hour an additional 30 drops of 30% potassium hydroxide in ethanol and 10 ml. of ethyl acrylate is added. The mixture is stirred for 2 hours and the solvent removed under vacuum. Toluene is added several times and the solvent removed. The residue is stirred with ether, filtered and the solvent evaporated to give ethyl γ-cyano-γ-[3-(trifluoromethyl)phenyl]-4-morpholinebutanoate (5.6 g.) as an oil. The oil is heated with 70% glacial acetic acid for 2 hours and the solvent removed. The residue is dissolved in dichloromethane and washed with water. The organic layer is dried (Na2SO4) and the solvent removed to give an oil. A mixture of the oil and 300 ml. of 6 N hydrochloric acid is refluxed for 5 hours, cooled and extracted with dichloromethane. The organic layer is extracted with sodium bicarbonate. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with dichloromethane. The extract is dried (Na 2 SO4) and the solvent removed. The residue is crystallized from hexane to give 3-[3-trifluoromethylbenzoyl]propionic acid as crystals, mp. 80°-82° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16]C)=O)(C)C.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Pb](SC#N)[S:30][C:31]#[N:32]>ClCCl>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([N:32]=[C:31]=[S:30])=[O:16])#[CH:5]
Reactant: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Reactant: N#CS[Pb]SC#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#Cc1ccccc1CC(=O)N=C=S
Reaction time: 1 h

Procedure:
To acid 319 (0.34 g, 2.1 mmol) in dry dichloromethane (25 mL) was added oxalyl chloride (0.39 mL, 0.57 g, 4.5 mmol) and dry DMF (0.05 mL). The mixture was stirred for 1 h, then concentrated under reduced pressure. The residue was re-dissolved in toluene (40 mL) and lead thiocyanate (0.75 g, 2.3 mmol) was added. The resulting suspension was heated to reflux with vigorous stirring for 3 h, then cooled, filtered through celite, and concentrated to afford crude 317 which was used without further purification.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.[CH3:34][C:35]([CH3:37])=O.[BH4-].[Na+]>ClCCCl.C(O)(=O)C.C(Cl)Cl>[Cl:33][C:18]1[C:19]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([CH:35]([CH3:37])[CH3:34])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc12
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
N-{(1R,2R)-2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (77 mg, 0.157 mmol) was placed in 1,2-dichloroethane (5 mL) and acetic acid (0.25 mL). Acetone (13.6 mg, 0.235 mmol, 17.2 μL, 1.5 eq) was added and the reaction was stirred for 5 minutes. Sodium borohydride (7.0 mg, 0.188 mmol, 1.2 eq) was added and the reaction was heated at 80° C. overnight. The reaction was then diluted with CH2Cl2 (20 mL) and washed with water (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by prep-HPLC using a gradient of 0-40% acetonitrile/water as the eluting solvent to obtain N-{(1R,2R)-2-[5-chloro-2-(10-Isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a mixture of diastereomers as an orange foam (14.63 mg, 17%). LCMS (m/e) 533 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.26-7.18 (m, 2H), 7.01 (d, 1H, J=6.7 Hz), 6.90 (bs, 1H), 5.49 (bs, 1H), 5.39-5.33 (m, 1H), 3.92-3.78 (m, 1H), 3.30-3.17 (m, 1H), 3.00-2.92 (m, 2H), 2.92-2.75 (m, 3H), 2.77 (s, 3H), 2.40-2.27 (m, 2H), 2.26-2.10 (m, 4H), 1.87-1.75 (m, 2H), 1.65-1.50 (m, 2H), 1.42-1.25 (m, 4H), 0.94 (d, 6H, J=6.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([O:9][CH2:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:10][CH2:11][C:12]3[CH:16]=[CH:15][S:14][C:13]=3[C:6]=2[N:7]=1
Reactant: Clc1ccc(OCCc2ccsc2)c(I)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: Clc1ccc2c(n1)-c1sccc1CCO2
Temperature: 80 °C
Reaction time: 3 h
Yield: 918.8 %

Procedure:
To a solution of 6-chloro-2-iodo-3-(2-(thiophen-3-yl)ethoxy)pyridine (9.14 g, 25.0 mmol) in acetonitrile (150 mL) was added tetraethylammonium chloride (4.14 g, 25.0 mmol), potassium carbonate (6.91 g, 50.0 mmol) and triphenylphosphine (1.31 g, 5.00 mmol) The reaction mixture was degassed and then charged with N2 three times. Palladium acetate (0.561 g, 2.50 mmol) was added to the reaction mixture. The reaction mixture was stirred under N2 at 80° C. for 3 h. The reaction mixture was diluted with DCM then filtered through celite. The filtrate was concentrated to get the crude product, which was purified by column on silica gel (EtOAc/Hexanes=1:10) to afford 54.6 g of 9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (Yield: 89%) 1H NMR (DMSO, 400 MHz): δ7.60 (d, J=5.2 Hz, 1H), 7.48 (d, J=6.0 Hz, 1H), 7.26 (d, J=6.0 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 4.32 (t, J=4.4 Hz, 2H), 3.20 (t, J=4.4 Hz, 2H). LC-MS (ESI): m/z=238 [M+H]
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH:7]([NH2:11])([CH2:9][CH3:10])[CH3:8]>C(O)C>[CH3:8][CH:7]([NH:11][CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:6])[CH2:9][CH3:10]
Reactant: C=CC(=O)NC
Reactant: CCC(C)N
Solvent: CCO
Product: CCC(C)NCCC(=O)NC
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
A mixture of N-methylacrylamide (ABCR; 500 mg, 5.87 mmol), sec-butylamine (Aldrich; 530 mL, 5.22 mmol) and ethanol (4 mL) was heated in a microwave to 140° C. for 45 minutes and then at 150° C. for 30 minutes. The reaction mixture was cooled and poured onto an SCX-2 cartridge (5 g) and cartridge washed through with methanol (˜50 mL). Products were then eluted with 2M ammonia in methanol (˜50 mL) and evaporated to afford the title compound as a straw coloured oil (563 mg; 61%)
Reaction SMILES: C[Si](C)(C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH3:14].F.[K].OO.O.C([O-])([O-])=[O:28].[K+].[K+]>CO.CCOC(C)=O>[CH3:14][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[OH:28]
Reactant: O=C([O-])[O-]
Reactant: CN1CCCC1c1cnccc1[Si](C)(C)c1ccccc1
Agent: F
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCCC1c1cnccc1O
Temperature: 55 °C
Yield: 82 %

Procedure:
To a solution of II (0.9 g, 3.2 mmol) in 10 mL of methanol was added potassium hydrogen fluoride (0.25 g, 3.2 mmol). A solution of 30% hydrogen peroxide in water (0.88 mL, 7.7 mmol) was slowly added, and the reaction mixture was stirred and heated at 55° C. for 8 h. To the crude mixture was added K2CO3 until the pH of the solution became slightly basic (pH 8-9). After filtration of the solid and evaporation of the solvent, the crude product was purified by radial PLC. (EtOAc) to yield 82% of III as a white solid. IR (neat) 2598, 23448, 1643 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1 H), 8.58-8.56 (m, 1 H), 8.12 (dd, 1 H, J=1.5 and 8 Hz), 7.47 (dd, 1 H, J=5.1 and 8 Hz), 4.61 (dd, 1 H, J=7.2 and 12 Hz), 3.79-3.59 (m, 2 H). 2.94 (s, 3 H), 2.72-2.1 (m, 4 H); 13C NMR (75 MHz, CD3OD) δ 170.5, 152.8, 151.4, 141.3, 124.9, 78.3, 71.4, 54.1, 29.5, 21.1. HRMS Calcd for C10H14N2O: 179.1184. Found: 179.1190 [M+H] +. [α]D25: +23.8 (c=0.8, MeOH). IR (neat) 2598, 23448, 1643 cm−1; 1H NMR (300 MHz,) δ 8.68 (s, 1 H), 8.58-8.56 (m, 1 H), 8.12 (dd, 1 H, J=1.5 and 8 Hz), 7.47 (dd, 1 H, J=5.1 and 8 Hz), 4.61 (dd, 1 H, J=7.2 and 12 Hz), 3.79-3.59 (m, 2 H), 2.94 (s, 3 H). 2.72-2.1 (m, 4 H); 13C NMR (75 MHz, CD3OD) δ 170.5, 152.8 151.4, 141.3, 124.9, 78.3, 71.4, 54.1, 29.5, 21.1. HRMS Calcd for C10H14N2O: 179.1184. Found: 179.1190 [M+H]+. [α]D25 +23.8 (c 8, MeOH).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([NH:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:19]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[Li+].ClCCl.S([O-])(O)(=O)=O.[Na+]>CO.O>[C:29]([O:28][C:26]([NH:25][CH2:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][C@H:4]([CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[C:3]([OH:34])=[O:2])=[O:33])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)N[C@H](Cc2ccc3ccccc3c2)C(=O)O)c1
Yield: 92.2 %

Procedure:
(R)-2-(3-(tert-Butoxycarbonylaminomethyl)benzoylamino)-3-(2-naphthyl)propionic acid methyl ester (8.8 g, 19.1 mmol) was dissolved in methanol (100 ml) and lithium hydroxide (0.55 g, 22.2 mmol) was added. After 2 h dichloromethane (200 ml), water (200 ml) and 3 M sodium hydrogen sulfate (50 ml) were added. The organic phase was separated and washed with water (100 ml). The organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to yield 7.9 g of (R)-2-(3-(tert-butoxycarbonylaminomethyl)benzoylamino)-3-(2-naphthyl)propionic acid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 74.5 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 1.22 ml (4.96 mmol) of myristoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.17 g of the desired compound (74.5%, colorless powder), mp: 80.0°-81.0° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[C:5]2[O:10][C:11](=[O:14])[O:12][CH2:13][C:4]=12.CCOC(S)=[S:19]>>[SH:19][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[C:5]2[O:10][C:11](=[O:14])[O:12][CH2:13][C:4]=12
Reactant: CCOC(=S)S
Reactant: Cc1ncc(CCl)c2c1OC(=O)OC2
Product: Cc1ncc(CS)c2c1OC(=O)OC2

Procedure:
5-Chloromethyl-8-methyl-2-oxo-4H-m-dioxino[4,5-c]pyridine is converted to the corresponding ethyl xanthogenate and reduced in accordance with the procedure of Example 19, Step B, to give 5-mercaptomethyl-8-methyl-2-oxo-4H-m-dioxino[4,5-c]pyridine.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:25]1[S:26][C:27]([N:30]2[CH2:34][N:33]=[C:32]([CH3:35])[O:31]2)=[CH:28][CH:29]=1.[Cl-].[NH4+]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:25]4[S:26][C:27]([N:30]5[CH2:34][N:33]=[C:32]([CH3:35])[O:31]5)=[CH:28][CH:29]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Reactant: CC1=NCN(c2ccc(Br)s2)O1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3ccc(N4CN=C(C)O4)s3)CCC(=O)CC2)cc1OC1CCCC1

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-one (0.17 g, 0.88 mmol) and 2-bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene (0.18 g, 1.2 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.037 g, 4%) and copper(I) iodide (0.010 g, 6%), and the mixture was heated at 85°-90° C. for 2 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-one as a white wax (0.17 g, 45%), mp 94°-95° C. Anal. (C27H28N2O4S) calcd: C, 68.04; H, 5.92; N, 5.88; found: C, 67.83; H, 5.89; N, 5.92.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C1COCC1.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>[F:1][C:2]1[CH:22]=[C:21]([C:26]#[C:25][CH2:24][OH:27])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)NCCO)c(Nc2ccc(I)cc2F)cc1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Yield: 79 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with propargyl alcohol in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a cream solid (79%). 1H NMR [(CD3)2SO, 400 MHz] δ 10.26 (s, 1H), 8.44 (t, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.38 (dd, J=11.6, 1.8 Hz, 1H), 7.27 (dd, J=8.3, 1.4 Hz, 1H), 5.70 (s, 1H), 5.35 (t, J=5.9 Hz, 1H), 4.76 (t, J=5.7 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 3.50 (q, J=5.8 Hz, 2H), 3.38 (s, 3H), 3.31-3.26 (m, 2H). LCMS (APCI+) calcd for C18H18FN3O4 360 (MH+), found 360.
Reaction SMILES: [CH:1]([C:3]1[C:16]([O:17]C)=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2].B(Cl)(Cl)Cl.C([O-])(=O)C.[Na+]>ClCCl.C(OCC)(=O)C.C(Cl)(Cl)Cl.CO>[CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: COc1cccc(OCCCCC(=O)O)c1C=O
Agent: CC(=O)[O-]
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=Cc1c(O)cccc1OCCCCC(=O)O
Temperature: -70 °C

Procedure:
5-(2-Formyl-3-methoxyphenoxy)pentanoic acid (504 mg., 0.002 M) was dissolved in anhydrous dichloromethane (20 ml.) and cooled to -70° C., with stirring. A solution of boron trichloride in anhydrous dichloromethane (0.25 g/ml., 3.76 ml., 0.94 g, 0.008 M) was added dropwise over 10 mins. and the mixture stirred at -70° C. (15 mins). The reaction mixture was allowed to reach ambient temperature and stirred at that temperature (1.25 hrs). After cooling to 10° C., 10% sodium acetate solution (15 ml.) was added dropwise with stirring so that the temperature did not rise above 15° C. The resulting mixture was diluted with ethyl acetate (50 ml.) and filtered. The filtrate was transferred to a separating funnel and the aqueous layer separated. The organic phase was extracted with 10% sodium carbonate solution (2×50 ml.), the combined extracts acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried (sodium sulphate) and evaporated to give a crystalline solid. This solid was dissolved in the minimum of chloroform-methanol (95:5) and passed through a pad of Kieselgel G. Evaporation of the filtrate and recrystallisation from benzene-petrol gave 5-(2-formyl-3-hydroxyphenoxy)pentanoic acid, m.p. 97°-99° C. (Found: C, 60.42; H, 6.15. C12H14O5 requires C, 60.50; H, 5.92%).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH2:17])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:18][CH2:19][C:20]([CH2:22]Cl)=O>>[Cl:18][CH2:19][C:20]1[N:17]=[C:15]([CH:14]=[C:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[O:16][CH:22]=1
Reactant: NC(=O)C=C1c2ccccc2-c2ccccc21
Reactant: O=C(CCl)CCl
Product: ClCc1coc(C=C2c3ccccc3-c3ccccc32)n1
Yield: 36 %

Procedure:
In substantially the same manner as in Reference Example 47, 9-fluorenylideneacetamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(9-fluorenylidene)methyloxazole. The yield was 36%. Recrystallization from ethyl acetate-hexane gave yellow prisms, mp 175-176° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]=[C:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1.O.[OH-].[Na+]>C(OCC)C>[NH2:15][CH2:14][C:11]1([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:21]=2)[CH2:10][CH2:9][CH:8]([OH:7])[CH2:13][CH2:12]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCC(=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
To a stirred suspension of LiAlH4 (0.59 g, 15 mmol, 10 eq) in diethyl ether (8 mL) was added dropwise at ambient temperature a solution of 4-oxo-1-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarbonitrile (0.5 g, 1.5 mmol) in diethyl ether (25 mL). The reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to 0° C. and, successively, a solution of water, sodium hydroxide (15% w/v, 0.68 mL) and water again were carefully added dropwise. After being stirred for 15 min at room temperature, the mixture was filtered over diatomaceous earth and concentrated. The residue was purified by flash chromatography (10 g silica gel, DCM/MeOH (10% NH3) to provide the title compound (0.27 g, 54%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][C:18]=1[N+:30]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].O>[NH2:30][C:18]1[CH:19]=[C:20]([CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]3[CH:34]=[C:35]([F:37])[CH:36]=[C:2]([F:1])[CH:3]=3)[CH:7]=2)[NH:11][N:10]=1)=[O:33]
Reactant: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(CN2CCCCC2)cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Nc1cc(CN2CCCCC2)ccc1C(=O)Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Reaction time: 2 h
Yield: 103.3 %

Procedure:
N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-nitro-4-piperidin-1-ylmethyl-benzamide (255 mg, 0.505 mmol) was suspended in DCM (7 mL) and treated with nBu4NCl (95 mg, 0.343 mmol). Na2S2O4 (659 mg, 3.029 mmol) in water (3.4 mL) was added drop-wise, with stirring. After 2 hours, the volatiles were removed by evaporation, a solid was filtered from the aqueous phase and dried under vacuum. The solid was treated with 4N HCl in dioxane (12 mL) and the solvent was then removed by evaporation. The solid was dissolved in DCM (100 mL), washed with aqueous K2CO3 and then with brine. After drying over sodium sulphate and removal of the solvent, 248 mg of title compound were obtained in more than quantitative yield. The crude was employed in the following step with no further purification.
Reaction SMILES: [H+].[B-](F)(F)(F)F.Cl.[CH3:8][C:9]1[CH:17]=[CH:16][C:15]2[NH:14][C:13]3[CH2:18][CH2:19][NH:20][CH2:21][C:12]=3[C:11]=2[CH:10]=1>[Pt](=O)=O.O>[CH3:8][C:9]1[CH:17]=[CH:16][C:15]2[NH:14][CH:13]3[CH2:18][CH2:19][NH:20][CH2:21][CH:12]3[C:11]=2[CH:10]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CNCC3
Agent: O=[Pt]=O
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Product: Cc1ccc2c(c1)C1CNCCC1N2
Yield: 87.2 %

Procedure:
To a mixture of water (50 ml) and 42 % borofluoric acid (18 ml) is added 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (5.7 g), and the mixture is subjected to a catalytic reduction under heating in the presence of platinum dioxide (0.2 g). When hydrogen (820 ml) is absorbed, the catalyst is filtered off and the filtrate is made alkaline with aqueous ammonia, salted out with potassium carbonate and extracted with benzene. The benzene layer is washed with water, dried over anhydrous sodium sulfate and concentrated to give the titled compound (4.2 g), m.p. 73° - 75°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:22][NH2:23]>CO>[NH:22]([C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:23]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (Aldrich, 300 mg, 1.07 mmol) in MeOH (5.4 mL) was added hydrazine hydrate (170 μL, 3.44 mmol). The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was triturated with hexanes (2×) and then from a minimal amount of 2:3 hexanes/MeOH (2×) to give the title compound (195 mg, 65%) as a white solid. 1H NMR (CDCl3) δ 7.41-7.25 (m, 3H), 7.20 (d, J=6.8 Hz, 2H), 4.39-4.21 (m, 1H), 3.07 (d, J=7.0 Hz, 2H), 1.42 (s, 9H); MS (ESI+) m/z 280.3 (M+H)+.