Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].OO.C(=O)([O-])[O-:12].[Na+].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[N+:5]([O-:12])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cccnc1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1ccc[n+]([O-])c1
Temperature: 80 °C

Procedure:
A mixture of 10.0 g of 3-ethylpyridine, 60 ml of acetic acid and 12 ml of 30% hydrogen peroxide solution was stirred while heating at 80° C. for 2.5 hours. To the reaction mixture, 7 ml of 30% hydrogen peroxide solution was added, and the reaction mixture was stirred while heating at 80° C. for further seven hours. The reaction mixture was cooled to room temperature, and sodium carbonate was added to the reaction mixture in small portions. The reaction mixture was filtered, and washed with ethyl acetate. The resultant filtrate was washed with a saturated aqueous solution of sodium hydrogen sulfite and a saturated sodium chloride solution, dried over anhydrous water sodium carbonate. Activated carbon was added, followed by filtration through Celite™. The filtrate was concentrated under reduced pressure to give 6.0 g of 3-ethylpyridine N-oxide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:35])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][C:30]([O:32]CC)=O)=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[CH2:36][CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][NH:47][CH3:48]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:35])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][C:30]([N:47]([CH3:48])[CH3:46])=[O:32])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[CH2:36][CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2
Solvent: C1CCOC1
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2

Procedure:
Ethyl 2-[(2S)-2-[[(2RS)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (256 mg) and 2.2 ml of dimethylamine were dissolved in 2.2 ml of tetrahydrofuran, and the solution was sealed in a tube and subjected to 39 hours of reaction at 60° C. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: ethyl acetate/ethanol=1/1) to give 230 mg of amorphous 2-[(2S)-2-[[(2RS)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH2:20][CH3:21].B(Br)(Br)Br.ClCl>>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1cc2c(OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Agent: ClCl
Product: CCCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 71.1 %

Procedure:
By the method used in Example 1, Part D, 1.16 g (3.27 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-4-methoxy-2-propyl-1H-indole was O-demethylated by treating it with 13 mL of 1M BBr3 /CH2 Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 794 mg (71% yield) of 1-([1,1'-biphenyl]-2-ylmethyl)-4-hydroxy-2-propyl-1H-indole as an oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=O)[O:24][C:25]=1[CH3:26]>>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[O:24][C:25]=1[CH3:26]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cc1cc(C=O)oc1C
Product: Cc1cc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)oc1C

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4,5-dimethylfuran-2-carbaldehyde was carried out according to General Synthetic Method 6. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4,5-dimethylfuran-2-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]2=[O:17].[CH2:18](Br)[CH2:19][CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]2=[O:17]
Reactant: CC(C)CCBr
Reactant: CCOC(=O)c1cc(=O)c2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(=O)c2cc(OCCC(C)C)ccc2s1

Procedure:
A mixture of 9 parts of ethyl 6-hydroxy-1-thiachromone-2-carboxylate, 15 parts of isoamyl bromide and 14 parts of anhydrous potassium carbonate in 130 parts of acetone was stirred and heated under reflux for 18 hours. Insoluble material was then filtered off and washed with acetone and the total acetone solution was evaporated to leave a yellow solid, which was crystallized from ethanol to give 4.1 parts of ethyl 6-(3-methylbutoxy)-1-thiachromone-2-carboxylate, melting point 83°-84°C. This entire product was heated under reflux for 2 hours with a solution of 1.5 parts of sodium bicarbonate in 35 parts of water and 25 parts of methanol. The methanol was then boiled off and the solution was diluted with 70 parts of water. The aqueous solution was thoroughly washed with ether, filtered then acidified with concentrated hydrochloric acid. A precipitate was obtained which was filtered off, washed with water and dried, then extracted with boiling benzene. The product was then filtered off and dried to leave 3.95 parts of 6-(3-methylbutoxy)-1-thiachromone-2-carboxylic acid, melting point 208°-209°C.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:35])[NH:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:22][C:21]1[CH:20]=[C:19]([C:23](=[O:35])[NH:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)[S:18][C:17]=1[C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[C:3]([OH:36])=[O:2])=[O:16]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-({3-Chloro-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (48.7 mg, 0.089 mmol) in THF (2 mL) was added a solution of lithium hydroxide monohydrate (37 mg, 0.89 mmol) in water (3 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 34.8 mg (73%). MS m/e 531.9 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:4]=1.[BH4-].[Na+].Cl>CS(C)=O>[CH2:8]([C:5]1[CH:4]=[C:3]([CH3:2])[O:7][N:6]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCc1cc(CBr)on1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCc1cc(C)on1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 5-(bromomethyl)-3-dodecylisoxazole (9.99 g, 0.0302 mol) in dimethylsulfoxide (100 mL) was warmed to give a cloudy solution and allowed to cool. When the temperature reached +35° C., sodium borohydride (1.2 g, 0.032 mol) was added in one portion, and the mixture was stirred for 3 days under nitrogen at room temperature. The mixture was poured into 0.1M HCl (900 mL) and extracted with ether. The organic layer was washed (saturated NaCl), dried (MgSO4), and rotoevaporated. The residue was chromatographed on silica gel (160 g, 70-230 mesh) using petroleum etheracetone (29:1, 10×200 mL) as eluent. Fraction 6 was rotoevaporated and dried in vacuo to give a white solid; yield 3.96 g (52%); mp 35°-38° C.
Reaction SMILES: [NH2:1][C:2]1[O:7][C:6]2[C:8]3[C:13]([CH:14]=[CH:15][C:5]=2[CH:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=2)[C:3]=1[C:24]#[N:25])=[CH:12][CH:11]=[CH:10][CH:9]=3>C(OCC)(OCC)OCC>[Cl:23][C:18]1[CH:17]=[C:16]([CH:4]2[C:3]([C:24]#[N:25])=[C:2]([N:1]=[CH:2][O:7][CH2:6][CH3:5])[O:7][C:6]3[C:8]4[C:13]([CH:14]=[CH:15][C:5]2=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: N#CC1=C(N)Oc2c(ccc3ccccc23)C1c1ccc(F)c(Cl)c1
Solvent: CCOC(OCC)OCC
Product: CCOC=NC1=C(C#N)C(c2ccc(F)c(Cl)c2)c2ccc3ccccc3c2O1
Reaction time: 24 h

Procedure:
2-Amino 4 (3-chloro-4-fluorophenyl)-4H-naphtho[1,2-b]pyran-3-carbonitrile (3.12 g) was heated, under reflux, in triethyl orthoformate (40 ml) for 24 hours. A fraction coming over at 80° to 140° C. was distilled off and more triethyl orthofomate (40 ml) was added, and the refluxing was continued for a further 24 hours. The solution was evaporated to dryness. The gummy residue was dissolved in chloroform and passed through a column of `flash` silica using 30% hexane in chloroform as eluant. The fractions containing product were bulked, evaporated and triturated with ethyl acetate to give white crystals of 4-(3-chloro-4-fluorophenyl)-2-ethoxymethyleneamino-4H-naphtho[1,2-b]pyran-3-carbonitrile, m.p. 146°-148° C.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=[O:6])[CH3:5].[CH3:8][O:9][C:10]1[CH:20]=[CH:19][C:13]([CH2:14][NH:15][C:16]([NH2:18])=[S:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>CO>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][NH:15][C:16]2[S:17][C:3]([C:4](=[O:6])[CH3:5])=[C:2]([CH3:1])[N:18]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CNC(N)=S)cc1
Reactant: CC(=O)CC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(CNc2nc(C)c(C(C)=O)s2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 3-chloro, 2,4-pentanedione (1.0 g, 7.43 mmol) and 1-(4-methoxy benzyl)-2-thiourea (1.46 g, 7.43 mmol) in methanol (10 ml) is treated with pyridine (0.6 ml). The reaction mixture is stirred at room temperature for 2 hours and then the solvent is removed in vacuo. The crude residue is triturated with ether to yield the titled compound as a white solid.
Reaction SMILES: [CH:1]([P:3](=[O:6])([OH:5])[OH:4])=O.[NH2:7][CH2:8][C:9]([OH:11])=[O:10]>[Pd]>[CH2:8]([NH:7][CH2:1][P:3]([OH:4])([OH:5])=[O:6])[C:9]([OH:11])=[O:10]
Reactant: O=CP(=O)(O)O
Reactant: NCC(=O)O
Agent: [Pd]
Product: O=C(O)CNCP(=O)(O)O
Yield: 34 %

Procedure:
Reaction of formylphosphonic acid and glycine was carried out in the manner described in Example 16 except that the catalyst was 1% palladium on alumina (0.5 g, 3.2 mm pellets). A 34% yield of glyphosate was obtained.
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:36])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:17])(OCC1C=CC=CC=1)=O.[ClH:37].[H][H]>[Pd].CC(O)C>[ClH:37].[NH2:11][CH2:12][C:13](=[O:36])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:17]
Reactant: O=C(CCC(=O)OCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NCC(=O)CCC(=O)OCCCCCCCC(=O)O
Yield: 69.2 %

Procedure:
This compound was prepared from the product of 10b (0.70 g; 1.4 mmol), 12 M HCl (0.12 mL; 1.4 mmol), 10% Pd/C (100 mg), hydrogen gas, and 2-propanol (25 mL) using the procedure in Example 8d. 0.30 g (70%) product was obtained (white solid).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C@@H:9]2[C@H:14]([CH2:15][OH:16])[CH2:13][CH2:12][O:11][CH2:10]2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](O)[C:19]=1[CH:20]=[O:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:16][CH2:15][C@@H:14]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=2)[C:19]=1[CH:20]=[O:21]
Reactant: CC(C)n1nccc1[C@H]1COCC[C@H]1CO
Reactant: O=Cc1c(O)cccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)n1nccc1[C@H]1COCC[C@H]1COc1cccc(O)c1C=O
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
To a solution of (±)((3S,4R)-3-(1-isopropyl-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-yl)methanol (50 mg, 0.22 mmol) and 2,6-dihydroxybenzaldehyde (60 mg, 0.44 mmol) in THF (1 mL) was added PPh3 (120 mg, 0.44 mmol) and DIAD (0.09 mL, 0.44 mmol) at 0° C. After stirred for 30 min, the solution was concentrated and the residue was purified by column (Hexanes/EtOAc=60:40) to give impure product, which was further purified by prep HPLC (eluted with ACN/H2O) to give (±) 2-hydroxy-6-(((3S,4R)-3-(1-isopropyl-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-yl)methoxy)benzaldehyde (6 mg). 1H NMR (400 MHz, CDCl3) (ppm) 11.90 (s, 1H), 10.36 (s, 1H), 7.79 (s, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.32 (t, J=8.8 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 6.43 (d, J=1.6 Hz, 1H), 6.16 (d, J=8.0 Hz, 1H), 4.46 (m, 1H), 4.13 (dt, J=11.2, 4.0 Hz, 1H), 3.95 (dd, J=11.2, 3.2 Hz, 1H), 3.81 (dd, J=11.6, 3.2 Hz, 1H), 3.73 (dd, J=9.2, 5.6 Hz, 1H), 3.65 (dt, J=11.6, 3.2 Hz, 1H), 3.57 (t, J=8.8 Hz, 1H), 3.28 (d, J=4.0 Hz, 1H), 2.56 (m, 1H), 1.87 (m, 1H), 1.58 (m, 1H), 1.31 (d, J=6.8 Hz, 3H), 1.29 (d, J=7.6 Hz, 3H); MS (ESI) m/z 334.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O.C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([Cl:24])=[O:20]
Reactant: Cc1cccc(C)c1C=CCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C=CCCCCCCCC(=O)Cl

Procedure:
A solution of 10-(2,6-dimethyl-phenyl)-dec-9-enoic acid (239 mg, 0.87 mmol), oxalyl chloride (0.11 mL, 1.3 mmol), and N,N-dimethylformamide (one drop) in dichloromethane (3 mL) was stirred at room temperature for 2 hours, then volatile material was removed by distillation to afford 10-(2,6-dimethyl-phenyl)-dec-9-enoyl chloride. This was redissolved in dichloromethane, then N,N-diisopropylethylamine (140 mg, 1.04 mmol) was added dropwise, followed by (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride. The reaction mixture was stirred at room temperature for 16 h, then washed with water. The organic layer was evaporated and the residue purified by preparative HPLC to afford (R)-4-dimethylamino-3-[10-(2,6-dimethyl-phenyl)-dec-9-enoylamino]-butyric acid benzyl ester.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH3:8][CH:9](O)[CH2:10][CH2:11][CH3:12]>>[CH3:8][CH:9]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(O)N1
Reactant: CCCC(C)O
Product: CCCC(C)OC1CCC(=O)N1

Procedure:
5.5 g of 5-hydroxy-pyrrolidin-2-one, 30 cm3 of 2-pentanol and 2.75 g of Amberlite-15 resin are agitated for 5 hours at ambient temperature. After filtering, the excess pentanol is distilled off under 1 mm Hg at 40° C. The residue is chromatograp:hed on silica, (eluent: ethyl acetate), and 3.7 g of the expected product is obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[Sn](CCCC)(CCCC)CCCC.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][C:14]1[C:13]([O:12][CH2:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:26]2[N:25]([CH3:24])[CH:29]=[CH:28][N:27]=2)[N:7]=3)=[CH:21][CH:20]=[C:19]([F:22])[C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 120 °C

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.10 g, 0.24 mmol) in 5 ml of anhydrous DMF was added 1-methyl-2-tributylstannanyl-1H-imidazole (0.120 g, 0.32 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.004 g, 0.0037 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. The reaction mixture was then cooled to room temperature, added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/hexane (40:60) as the eluent to provide the title compound as brick red solid (0.020 g, 20%). 1H NMR (DMSO-d6, 400 MHz): δ 3.14 (s, 3H), 5.67 (s, 2H), 7.07 (m, 1H), 7.28-7.37 (m, 2H), 7.87 (m, 2H), 8.28 (s, 1H), 8.53 (s, 1H) and 8.75 (br s, 1H). MS ES+ (402.22), HPLC (method I) Rt=12.05 min.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:10][CH2:11][OH:12])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CC(C)=O>[CH2:20]([O:9][C:4]1[C:3]([CH2:10][CH2:11][OH:12])=[C:2]([F:1])[C:7]([F:8])=[CH:6][CH:5]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1c(O)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OCCc1c(OCc2ccccc2)ccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
To a solution of 3,4-difluoro-2-(2-hydroxyethyl)phenol (460 mg, 2.64 mmol) in Acetone (10 mL) was added K2CO3 (730 mg, 5.28 mmol) followed by (bromomethyl)benzene (0.471 mL, 3.96 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford 2-(6-(benzyloxy)-2,3-difluorophenyl)ethanol (580 mg, 2.195 mmol, 83% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.46-7.34 (m, 5H), 6.99 (q, J=9.1 Hz, 1H), 6.67-6.59 (m, 1H), 5.09 (s, 2H), 3.86 (q, J=6.4 Hz, 2H), 3.05 (td, J=6.5, 1.7 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[CH3:18]C1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[S:12]1[C:11]2[CH2:18][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH2:8][CH2:9][C:10]=2[CH:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)NCCc1ccsc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccsc2C1

Procedure:
To a solution of tert-butyl[2-(3-thienyl)ethyl]carbamate in toluene was added paraformaldehyde (2 equi.) and catalytic amount of PTSA and reaction mixture was then refluxed in dean stark apparatus for 4 hrs. Reaction mass wan then concentrated and extracted with dichloromethane dried over sodium sulphate and evaporated to yield tert-butyl 4,7-dihydrothieno[2,3-c]pyridine-6(5H)— carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10]>Cl.O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH3:10]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CCc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of mossy zinc (10 g) and mercuric chloride (0.5 g) in coned HCl (0.5 mL) and water (5 mL) was shaken for 5 min. The aqueous layer was then decanted. To the residue was added concd HCl (7.5 mL) and water (7.5 mL) followed by 2′,5′-dichloroacetophenone (3.106 g, 16.43 mmol) and the suspension was refluxed for 4 h during which time, hourly addition of coned HCl (90.5 mL) was carried out. The resulting suspension was cooled to room temperature and the aqueous layer was decanted. The residual solid was washed with ether (3×30 mL). The aqueous layer was extracted with ether (3×50 mL). The combined ether layer was washed with brine, dried over anhydrous Na2SO4, and removed under vacuum. The residue was dried further under vacuum to obtain 2.664 g crude product, which was purified on silica gel (Texane) to obtain 0.813 g (28%) pure (1H NMR) title compound as a colorless liquid; 1H NMR (DMSO-d6) 1.23 (t, 3H, J=7.5 Hz), 2.73 (q, 2H, J=7.5 Hz), 7.09-7.27 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1(O)[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]1
Reactant: OC1(c2cccc(F)c2F)CCC=CCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(C2CCC=CCC2)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.9 %

Procedure:
In a 100 mL round-bottomed flask (t=g) was added (Z)-1-(2,3-difluorophenyl)cyclohept-4-enol (872 mg, 3.89 mmol) in CH2Cl2 (16 mL) to give a colorless solution. Triethylsilane (3.11 mL, 19.44 mmol) was added, following by TFA (8.00 mL). The mixture was stirred at room temperature for 2.5 hours. TLC showed clean conversion to a less polar compound. It was concentrated down and purification by FCC up to 20% Et2O in hexane afforded the desired product as a colorless oil (769 mg, 95%). The product was quickly eluted out. 1H NMR (the major peaks are the same as these in the later synthesis) confirmed the structure.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6]1([CH3:9])[CH2:8][NH:7]1>C(COC)OC>[NH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][S:1][CH2:2][CH2:3][OH:4]
Reactant: OCCS
Reactant: CC1(C)CN1
Solvent: COCCOC
Product: CC(C)(N)CSCCO
Temperature: 70 °C
Reaction time: 4 h

Procedure:
234 g of 2-mercaptoethanol are dissolved in 90 ml of dimethoxyethane. 63.3 g of 2,2-dimethylaziridine are added dropwise to this solution and the mixture is stirred at 70° C. for 4 hours and concentrated, and the residue is distilled in a water jet vacuum. B.p.: 141°-142° C. (at 20 mbar); M.p.: 49°-51°;
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:28][CH:27]([OH:29])[CH:26]=[CH:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:24]3[CH2:25][CH2:26][CH:27]([OH:29])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1C=CC(O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(O)C1

Procedure:
4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopent-2-enol (110 mg) was hydrogenated in ethanol (20 ml) with gaseous hydrogen at atmospheric pressure using 10% palladium on charcoal (50 mg) as the catalyst. The catalyst was removed by filtration and the filtrate was evaporated to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol, as an oil. The structure was confirmed by 1H nmr and mass spectra.