Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([NH:23]C(=O)OCC=C)[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([CH:20]=[CH:21][CH:22]=2)[NH2:23])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
In a round bottom flask 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (800 mg, 1.79 mmol) was dissolved in DCM (30 mL) and water (0.5 ml). Tri-n-butyltin hydride (0.480 mL, 1.79 mmol) was added followed by tetrakis(triphenylphosphine)palladium (0) (103 mg, 0.090 mmol). This mixture was stirred 3 h at rt. By TLC all starting material is consumed. The reaction was concentrated to dryness. The crude was then dissolved into a small amount of DCM and injected onto a 25 g silica gel column. The column was eluted with EtOAc and hexanes. The title compound was obtained (0.594 g, 1.47 mmol, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (d, J=5.3 Hz, 1H), 6.96-7.08 (m, 2H), 6.91 (t, J=8.2 Hz, 1H), 6.64 (t, J=6.7 Hz, 1H), 5.33 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].IC.[C:22](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([NH:7][C:8]([N:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:22])[C:11]1=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCNC(=O)n1c(=O)[nH]c2ncccc21
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCCCNC(=O)n1c(=O)n(C)c2ncccc21

Procedure:
In 2.5 ml of DMF, N-hexyl-2-oxo-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxamide (65 mg, 0.248 mmol), iodomethane (70 mg, 0.5 mmol) and cesium carbonate (80 mg, 0.25 mmol) were stirred at RT for 5 h. After concentration, the mixture was admixed with water and ethyl acetate, and the organic phase was removed, concentrated and purified by means of preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 16 mg (23%), M+H+: 277.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](N)=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[OH-:20].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:20])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: NC(=O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1

Procedure:
A mixture of 2,2',4'-trifluoro-4-biphenylylacetamide (100 mg.), aqueous caustic soda (18N; 1 ml.) and water (5 ml.) was stirred under reflux overnight. The mixture was acidified and extracted with ether. The ether was evaporated and the product recrystallised from 80-100 petroleum ether to give 2,2',4'-trifluoro-4-biphenylylacetic acid, m.p. 144°-147° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21](I)[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cu][C:31]#[N:32]>O1CCCC1.C(OCC)(=O)C.[Cu]I.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>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([C:31]#[N:32])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: N#C[Cu]
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reaction time: 1 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (10 mL) was added copper(I) iodide (180 mg, 0.094 mmol), tetrakis(triphenyphosphine)palladium(0) (5.4 mg, 0.047 mmol) and copper(I) cyanide (420 mg, 4.7 mmol) sequentially at room temperature. After heating the reaction mixture at reflux overnight, additional copper(I) cyanide (420 mg, 4.7 mmol), copper(I) iodide (107 mg, 0.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (325 mg, 0.28 mmol) were added and the reflux was continued for 1 hour. The reaction mixture turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was then diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 410 mg of the title compound as a crude yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:11][CH:10]=1>ClC(Cl)(Cl)Cl>[Br:1][C:16]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[NH:23][C:15]=1[C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cnc2cc(-c3ccncc3)[nH]c2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c(-c2ccncc2)[nH]c2cccnc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
800 mg of N-bromosuccinimide (4 mmole) is added to a solution of 720 mg (3.7 mmoles) of 2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine in tetrachloromethane. The brown reaction mixture is stirred 5 hours at 50° C. and concentrated. The brown residue is purified by chromatography on silica gel (ethylacetate/methanol 9/1) to give 650 mg of 3-Bromo-2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1F
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1F
Temperature: 100 °C
Yield: 65.9 %

Procedure:
(S)-1-[6-Fluoro-1-(2-fluorophenyl)-1H-benzoimidazol-2-yl]ethylamine (0.22 g, 0.81 mmol) was dissolved in n-butanol (5 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.193 g, 0.81 mmol) and DIPEA (0.70 mL, 4.03 mmol) added. The reaction mixture was heated at 100° C. overnight. The resultant mixture was allowed to cool to RT and then concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH to afford a light yellow gum. This was purified by column chromatography (silica gel, gradient 0-5% MeOH in DCM) to afford 195 as an off-white solid (209 mg, 67%). LCMS (Method K): RT 3.34/3.52 min [M+H]+ 392.0 1H NMR (DMSO-d6, 400 MHz): δ 8.16-7.79 (3H, m), 7.77-7.64 (2H, m), 7.58-7.21 (3H, m), 7.16-7.09 (1H, m), 6.92-6.83 (1H, m), 5.63-5.38 (1H, m), 1.69 (1.5H, d, J=6.85 Hz), 1.58 (1.5H, d, J=6.86 Hz). NMR signals represent a mixture of rotamers
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:30]=1>CN(C=O)C>[Cl:20][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH2:28][C:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:30]=3)[N:17]=[N:18][C:19]=2[C:11]=1[O:10][C:8]1[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (0.006 g, 0.020 mmol) and cesium carbonate (0.0077 g, 0.024 mmol) suspended in DMF (1 mL) at room temperature was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (=Intermediate 1; 0.0068 g, 0.022 mmol) as a solution in DMF (0.5 mL). After stirring for 1 hour at room temperature, the reaction mixture was quenched with aqueous ammonium chloride (2 mL), and the quenched mixture was extracted with ethyl acetate (2×10 mL). The combined organic fractions were washed with water (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was subjected to automated silica gel chromatography eluting with a gradient of 25-50% ethyl acetate in hexanes to afford the title product. LRMS (M+1)=435.7
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[C:22]([Cl:24])[CH:23]=1>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: Clc1cc(Cl)cc([Mg]Br)c1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2cc(Cl)cc(Cl)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 0.5 M 3,5-dichlorophenylmagnesium bromide in THF (0.6 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(3,5-dichloro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11](OCC)=[O:12])=[CH:8][CH:7]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=2.C([O-])=O.[NH4+].[CH:24]([NH2:26])=O>O>[OH:12][C:11]1[C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:8]=3)[NH:3][C:2]=2[N:1]=[CH:24][N:26]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)[nH]c2cc(C(=O)OC)ccc12
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: COC(=O)c1ccc2c(c1)[nH]c1ncnc(O)c12
Temperature: 165 °C
Yield: 107.9 %

Procedure:
In a 100 mL round-bottom flask were added 3-ethyl 6-methyl 2-amino-1H-indole-3,6-dicarboxylate (1.1 g, 4.19 mmol), ammonium formate (0.53 g, 8.39 mmol), and formamide (16.7 mL, 419 mmol) to give a tan suspension which was heated to 165° C. for 12 hours. The mixture was allowed to cool to room temperature and water was added. The resulting precipitate was filtered, air-dried and dried under high vacuum overnight to afford 1.1 g of the title compound. LCMS m/z 244.2 (M+H)+, retention time (on analytical HPLC)=1.51 minutes.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C(#N)C>[CH:14]1([NH:17][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]2[C:12]#[N:13])=[O:4])[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CC1
Reaction time: 8 h

Procedure:
To a stirred solution of Example 8D (0.045 g, 0.228 mmol) in acetonitrile (2 mL) at room temperature under nitrogen was added cyclopropylamine (0.032 ml, 0.457 mmol). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 3% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS m/z 218 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.5-2 (4H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1>CN1C(=O)CCC1>[OH:38][CH:36]1[CH2:37][N:34]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:35]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OC1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CC(O)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and azetidin-3-ol in NMP. ES-MS m/e (%): 442 (M+H+, 100).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccnc1C(=O)c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccnc1C(O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-3-methylpyridine (4.0 g) and sodium azide (6.7 g) in DMSO (80 ml) was stirred for 21 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (3.90 g) in THF (40 ml) was added dropwise to a suspension of aluminum lithium hydride (1.24 g) in THF (40 ml) at 0° C. The mixture was stirred at room temperature for 3 hours, water (1.24 ml), 15% aqueous solution of sodium hydroxide (1.24 ml) and water (3.72 ml) were sequentially and slowly added dropwise to the solution at 0° C. The mixture was stirred temperature for 16 hours at room temperature, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, to give (4-aminophenyl)(3-methylpyridin-2-yl)methanol (2.60 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH:22]([CH2:24]O)[CH2:21][C:20]2=[O:26])=[CH:15][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH:22]2[CH2:21][C:20](=[O:26])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)[CH2:23]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C1CC(CO)CN1c1ccc(F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(F)cc3)C2)cc1
Temperature: 0 °C
Yield: 73.1 %

Procedure:
4-Hydroxybenzoic acid methyl ester (0.20 g, 1.314 mmol), 1-(4-fluoro-phenyl)-4-hydroxymethyl-pyrrolidin-2-one (0.33 g, 1.577 mmol), Ph3P (0.345 g, 1.314 mmol) and triethyl amine (0.20 ml, 1.577 mmol) were mixed under argon atmosphere followed by the addition of the dry toluene (10 mL). The reaction mixture was cooled to 0° C. followed by addition of DIAD (0.3 mL, 0.788 mmol) drop wise. The reaction mixture was allowed to warm to room temperature and heated at 80° C. for 24 h. The reaction was quenched with 5% HCl (10 mL), extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to afford the crude product which was purified by flash column chromatography to obtain 4-[1-(4-fluorophenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid methyl ester (0.33 g, 73%) as a white solid.
Reaction SMILES: O[Li].O.[CH:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[OH:20])=[O:5]>O.C1COCC1>[CH:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[OH:20])=[O:5]
Reactant: CCOC(=O)c1cc2c(C=O)c(O)ccc2o1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(O)ccc2oc(C(=O)O)cc12
Temperature: 50 °C
Yield: 99.4 %

Procedure:
The solution of LiOH—H2O (1.26 g, 60 mmol) in H2O (15 mL) was added dropwise to the solution of ethyl 4-formyl-5-hydroxybenzofuran-2-carboxylate (4.6 g, 20 mmol) in THF (40 mL). The reaction mixture was heated to 50° C. for 2 h. After cooled to RT, the reaction mixture was concentrated, then acidified with 3 M HCl to pH=2. The formed precipitate was filtered and washed with water, dried to give 4-formyl-5-hydroxybenzofuran-2-carboxylic acid (4.1 g. 87.8% yield). 1HNMR (DMSO, 400 MHz): δ 10.91 (s, 1H, OH), 10.47 (s, 1H, CHO); 7.92 (d, 1H, J=0.8 Hz, ArH), 70.87 (dd, 1H, J=9.2 Hz, 0.8 Hz, ArH), 7.13 (d, 1H, J=9.2 Hz, ArH); MS [ESI, MH+]: 207.1.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na].[OH-:21].[Na+]>N1C=CC=CC=1>[CH2:1]([S:19][CH:2]([CH3:1])[CH2:3][CH2:4][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: [OH-]
Agent: [Na+]
Agent: [Na]
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCSC(C)CCO
Yield: 12 %

Procedure:
The starting material is obtained as follows: Butylene-1,3-glycol is reacted with acetic anhydride at ambient temperature to give butane-1,3-diol 1-acetate in a yield of 63% of theory. It is then esterified with benzenesulphochloride in the presence of pyridine and the reaction product is eluted over a silica gel column with diethyl ether-ligroin (1:1 v/v). There is obtained a yield of 24% of theory of a colourless oil which is reacted with sodium octadecanethiol in the manner described in Example 20B and then treated with a dilute aqueous solution of sodium hydroxide to give a yield of 12% of theory of 3-octadecylthiobutanol; m.p. 35°-38° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[CH:17][C:16]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]O)[CH:29]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:14][C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[CH:17][C:16]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:29]=1
Reactant: Cc1cc(OC2CCCCO2)ccc1-c1cccc(CO)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OC4CCCCO4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (1.43 g, 7.94 mmol), [2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methanol (2.37 g, 7.94 mmol) and tributylphosphine (2.97 mL, 11.9 mmol) in toluene (120 mL) was stirred under ice-cooling and 1,1′-(azodicarbonyl)dipiperidine (3.00 g, 11.9 mmol) was added by small portions. The mixture was warmed to room temperature and stirred for 24 hrs. Hexane (60 mL) was added to the reaction mixture and the precipitated insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound as a colorless oil (3.05 g, yield 83%).
Reaction SMILES: O.[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[CH:7]1[C:2]([OH:8])=[CH:3][CH:4]=[C:5]([S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Solvent: O
Product: O=S(=O)(O)c1ccc(O)cc1

Procedure:
Phenolsulfonic acid solution was prepared in sulfuric acid. The method included setting up a recirculating water bath so that the water was at a temperature of 95 degrees Centigrade. Next, the weight of available stock of Liquified Phenol USP containing 3.23 moles of Phenol was calculated. Phenol has a molecular weight of 94.11. The weight of 3.23 moles of Phenol is 3.23×94.11+303.97 grams. The purity of Liquified Phenol USP typically ranges from 89.0% to 91.5%. Using the purity value either from the manufacturer's Certificate of Analysis or the purity value from an internal quality control analysis, the weight of the available stock of Liquified Phenol USP required to deliver 3.23 moles of Phenol was calculated.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[C:12]([C:25]2([O:30][CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:11]=1)(C)C)(C)(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[F:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]=1[C:25]1([O:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C2(OC)CCCC2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2(OC)CCCC2)c1
Reaction time: 16 h
Yield: 54 %

Procedure:
To a solution of 66.68E (66 mg, 168 μmol) in MeOH, was added PPTS (11 mg, 45 μmol), and the mixture was stirred for 16 hours. Solvent was then removed in vacuo to give a residue which was purified by Combiflash chromatography to give the product as an oil (30 mg, 61%). MS ESI m/e: 331.2 (M+H)+.
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[CH:6]=[C:7]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:24])=[C:20](Cl)[N:21]=3)[C:16](=[O:25])[C:15]([C:26]([OH:28])=[O:27])=[CH:14]2)[C:8]([F:12])=[CH:9][C:10]=1[F:11].Cl.Cl.[NH2:31][CH:32]1[CH2:35][NH:34][CH2:33]1>C(N(CC)CC)C>[NH2:31][CH:32]1[CH2:35][N:34]([C:20]2[N:21]=[C:22]3[C:17]([C:16](=[O:25])[C:15]([C:26]([OH:28])=[O:27])=[CH:14][N:13]3[C:7]3[C:8]([F:12])=[CH:9][C:10]([F:11])=[C:5]([NH2:4])[CH:6]=3)=[CH:18][C:19]=2[F:24])[CH2:33]1
Reactant: NC1CNC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)nc32)c(F)cc1F
Temperature: 80 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To 200 ml of acetonitrile were added 3.7 g of 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 2.18 g of 3-aminoazetidine dihydrochloride, and 6.06 g of triethylamine. The solution was stirred at 80° C. for 15 hours. The reaction solution was cooled whereupon the precipitated solid was collected by filtration and washed with ethanol and isopropyl ether to give 3.7 g of the title compound.