Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH:30]OS([O-])=O.[K+]>CO.O>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12](=[O:30])[CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN1CCSC(c2ccc(OCc3ccccc3)cc2)C1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCS(=O)C(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[2-(4-benzyloxy-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl ester (0.85 g; 1.77 mmol) in MeOH (25 mL) was added dropwise a solution of Oxone® (0.54 g; 0.89 mmol) in water (25 mL), at 0° C. The resulting mixture was stirred for 2 hours at 0° C., and subsequently, overnight at RT. The resulting mixture was treated with water and a 25% aqueous solution of NH4OH, and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 97.5:2.5) to afford 3-[2-(4-benzyloxy-phenyl)-1-oxo-thiomorpholin-4-yl]-propionic acid tert-butyl ester (0.65 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 4-fluorobenzyl bromide (1.2 eq.) and sodium hydride (1.5 eq.). ESI (m/z): 291 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][OH:27].[H-].[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[CH:8][CH:9]=1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(C)CCOc1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 12.6 %

Procedure:
In a similar fashion using route 51 general procedure 119, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (200 mg, 0.59 mmol), N,N-dimethyl ethanolamine (210 mg, 2.3 mmol), NaH (60% in mineral oil; 71 mg, 1.79 mmol) and NMP (2 ml) gave the title compound (30 mg, 13%) after purification by column chromatography with DCM/MeOH (98:2) elution.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:10]=2[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:33]=[C:32]([NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])(=[O:37])=[O:36])[CH:31]=[CH:30][C:29]=1[CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:34]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N+:44]([O-:46])=[O:45])(=[O:36])=[O:37])[C:32]3[CH:31]=[CH:30][C:29]([CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:28]([F:27])[CH:33]=3)=[CH:11][C:10]=2[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: CC(C)Cc1cc(CO)ccc1OC(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N(Cc2ccc(OC(c3ccccc3)c3ccccc3)c(CC(C)C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
To a solution of [4-(diphenylmethoxy)-3-isobutylphenyl]methanol (0.49 g, 1.41 mmol), ethyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (0.62 g, 1.56 mmol) and triphenylphosphine (0.55 g, 2.10 mmol) in tetrahydrofuran (25 mL) was added diethyl azodicarboxylate (40% toluene solution, 0.93 mL, 2.13 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=3/97-15/85) to give the title compound (800 mg, yield 78%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:25]([O:29][N:30]1N=NC2C=CC=C[C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[CH3:25][O:29][N:30]([CH3:31])[C:17]([C:16]1[CH:20]=[CH:21][C:13]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:12][CH2:11][CH2:10]2)=[CH:14][CH:15]=1)=[O:19]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)O)cc2)CCC1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of 4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoic acid (2.5 g, 1 eq.) in dimethylformamide (10 mL) was added HBTU (3.41 g, 1.05 eq.) followed by triethylamine (6 mL, 5 eq.). The reaction mixture was stirred at room temperature for 10 minutes then the N,O-dimethylhydroxylamine hydrochloride was added (4.3 g, 5 eq.) and the mixture was stirred for 3 days. The reaction mixture was poured onto water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (100 mL), brine (100 mL) then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (20-50% ethyl acetate in dichloromethane), giving tert-butyl (1-(4-(methoxy(methyl)carbamoyl)phenyl)cyclobutyl)carbamate (1.5 g, 52%). LCMS: 335 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[Br:1][C:2]1[C:8]([C:9]([F:10])([F:11])[F:12])=[CH:7][C:5]([NH:6][C:14](=[O:16])[CH3:15])=[C:4]([F:13])[CH:3]=1
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C(F)(F)F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A mixture of compound 22 (3.6 g, 14 mmol), acetic anhydride (8 mL) and pyridine (0.1 mL) was stirred at room temperature for 1 h, then concentrated in vacuo. The residue was added ice and sodium bicarbonate (until pH=7). The resulted mixture was extracted with EtOAc. The organic layers were combined, washed by brine, dried over Na2SO4, filtered and concentrated to give the title compound 23 (3.5 g, 83%). 1H NMR (400 MHz, CDCl3) δ8.79 (d, 1H, J=7.8 Hz), 7.46 (d, 1H, J=10.0 Hz), 7.38 (br s, 1H), 2.24 (s, 3H).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15]C=1C.S(=O)(=O)(O)O.[C:28]([OH:31])(=[O:30])[CH3:29]>O>[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:29]=1[C:28]([OH:31])=[O:30]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: CC(=O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 53 %

Procedure:
[25] To a solution of sodium dichromate (3.87 g, 13 mmol) in acetic acid (20 mL) was added 2-fluoro-4-nitrotoluene (1.55 g, 10 mmol) in portions, followed by dropwise addition of concentrated sulfuric acid (10 g). A strong exotherm was observed (100° C.) and the color changed from orange to green. The reaction was heated at 90° C. for 1 hour and cooled to 25° C. The reaction mixture was dissolved in water (30 mL) and white crystals formed upon cooling at 0° C. The white solid was collected by filtration washed with cold water and dried to give 2-fluoro-4-nitrobenzoic acid (0.99 g, 53%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[CH2:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:13]1[O:15][CH2:14]1>>[CH2:17]([O:16][CH2:12][C@H:13]([OH:15])[CH2:14][O:8][C@@H:6]1[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[CH:9]([CH3:11])[CH3:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: c1ccc(COC[C@H]2CO2)cc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC[C@@H](O)COCc1ccccc1

Procedure:
(2S)-3-{(1R, 2S, 5R)-[5-Methyl-2-(1-methylethyl)cyclohexyl]oxy}-1,2-propanediol represented by the following formula (I); ##STR1## a process of producing the (2S)-3-{(1R, 2S, 5R)-[5-methyl-2-(1-methylethyl)cyclohexyl]oxy}-l,2-propanediol which comprises adding (1R, 2S, 5R)-5-methyl-2-(1-methylethyl)cyclohexyl alcohol to (R)-(-)-benzyl glycidyl ether to provide (2S)-1-benzyloxy-2-hydroxy-3-{(1R, 2S, 5R)-[5-methyl-2-(1-methylethyl)cyclohexyl]oxy}propane, and hydrogenolyzing the product, are disclosed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].CC(C)([O-])C.[K+].Cl[CH2:18][C:19]([NH2:21])=[O:20]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH2:18][C:19]([NH2:21])=[O:20]
Reactant: NC(=O)CCl
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: NC(=O)COc1ccc(C=O)cc1Cl
Yield: 32.3 %

Procedure:
To a solution of 3-chloro-4-hydroxybenzaldehyde (10 g) in methanol (100 ml) was added 1.0 M potassium t-butoxide (64 ml). To the mixture was added 2-chloroacetamide (5.96 g) and the mixture heated under reflux overnight. The mixture was evaporated to the residue triturated with water (500 ml) and the solid collected to give the subtitle compound (4.4 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH3:14])[CH2:9][C:8]2=[O:15])[N:3]=[CH:2]1.[Cl:16]N1C(=O)CCC1=O>CC#N.C1COCC1>[Cl:16][C:5]1[N:1]=[CH:2][NH:3][C:4]=1[CH2:6][N:7]1[CH2:11][CH:10]([CH2:12][CH2:13][CH3:14])[CH2:9][C:8]1=[O:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCC1CC(=O)N(Cc2c[nH]cn2)C1
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCC1CC(=O)N(Cc2[nH]cnc2Cl)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
In a 100 ml, three-necked flask fitted with a magnetic stirrer and under inert atmosphere, 1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one 110 (500 mg, 2.4 mmol) is dissolved in a 1/1 mixture of CH3CN/THF (40 ml) and the solution is cooled to 0° C. N-chlorosuccinimide (410 mg, 3.1 mmol) is added by portions while the temperature is maintained at 0° C. The mixture is stirred for 18 h at this temperature. Most of the solvents are removed under vacuum and the residue is dissolved in 1N HCl and diluted with CH2Cl2. The first organic phase is removed and pH of the aqueous phase is adjusted to 9 by addition of solid Na2CO3. Then CH2Cl2 is added and the second organic phase is separated, dried over MgSO4 and concentrated to dryness. Purification by preparative chromatography on silicagel (eluent: CH2Cl2/MeOH/NH4OH: 95/05/0.5 (v/v/v)) affords 440 mg of 1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 126.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([CH:24]([C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[CH:31][CH:30]=[CH:29]5)[CH3:25])=[CH:22][N:23]=3)[N:20]=2)[CH:12]=[N:11]1.C(Cl)Cl.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CC#N>[N:32]1[C:33]2[C:28](=[CH:27][C:26]([CH:24]([C:21]3[N:19]4[N:20]=[C:15]([C:13]5[CH:12]=[N:11][N:10]([CH2:9][CH2:8][OH:7])[CH:14]=5)[CH:16]=[CH:17][C:18]4=[N:23][CH:22]=3)[CH3:25])=[CH:35][CH:34]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: CC(c1ccc2ncccc2c1)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(c1ccc2ncccc2c1)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask were introduced (rac)-6-[1-(6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-quinoline (Stage 177.1, 147 mg, 0.33 mmol) and DCM (4 mL), before adding dropwise HCl in dioxane (4 N, 0.248 mL). The RM was stirred at rt for 1 h and was then blown off with nitrogen. The residue was dissolved in water/CH3CN 1:1. The solution was basified with NaHCO3 (ca. 0.5 g) before being concentrated. The white suspension was filtered and the cake was washed with water, before being dried under vacuum. The crude was dissolved in MeOH/water and purified by preparative HPLC (H2O/CH3CN/TFA 1000:0:1 to 750:250:1 in 20 min.). Collected fractions containing the product were put together and basified with NaHCO3, before being concentrated. The resulting white suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid (tR 1.83 min (conditions 8), MH+=360).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH:6]=[C:5]2[CH3:12].ClC1C(=O)C(=O)C(Cl)=C(Cl)C=1Cl>>[F:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[C:5]2[CH3:12])=[CH:10][CH:11]=1
Reactant: CC1=CCCc2ccc(F)cc21
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Product: Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure A (Exp. 1.2.), 6-fluoro-4-methyl-1,2-dihydro-naphthalene was reacted with 3,4,5,6-tetrachloro-1,2-benzoquinone to give 7-fluoro-1-methyl-naphthalene as a colorless oil. MS: 160.1 ([M]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][C:9](=O)[NH:8]2)[CH:2]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1
Reactant: O=C1CCN(c2cccnc2)N1
Reactant: O=P(Cl)(Cl)Cl
Product: ClC1=NN(c2cccnc2)CC1

Procedure:
3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) may also be prepared through a three step, no isolation reaction sequence as disclosed in Scheme 6. In step a2, 3-hydrazinopyridine dihydrochloride is reacted with methyl acrylate in the presence of a base such as sodium methoxide or sodium ethoxide to yield 1-(pyridin-3-yl)pyrazolidin-3-one, followed by chlorination of 1-(pyridine-3-yl)pyrazolidin-3-one with phosphoryl chloride in a two-step process to yield 3-chloro-dihydropryazole (5a). In step b2, 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) is reacted with manganese (IV) oxide to yield the product (5b). Subsequent treatment of (5b) with an acid such as hydrochloric acid may provide the salt of the product (5b). The first step may be conducted in a polar protic solvent such as methanol or ethanol, at a temperature from about 40° C. to about 80° C. The second step may be conducted in a solvent such as chlorobenzene at a temperature from about 70° C. to about 90° C. The third step may be conducted in a solvent such as chlorobenzene at a temperature from about 70° C. to about 110° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](OC)=[O:12])=[N:9][N:8]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]2=[N:6][CH:7]=1.CCO.[Li+].[BH4-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][OH:12])=[N:9][N:8]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)cc12
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of methyl 5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XXII) (4.16 Kg, 8.3 mol) in anhydrous THF (62 L) cooled to 10° C. was added anhydrous EtOH (0.97 L, 16.6 mol) and LiBH4 (271 g, 12.5 mol). The reaction was warmed to room temperature and stirred for 24 hours. The solution was concentrated under vacuum to a volume of 4 L then taken up in DCM (80 L). The pH was then adjusted to 8.0 by dropwise addition of aqueous 0.4N HCl (˜280 L). The organic layer was separated and washed with aqueous 25% NaCl (28 L) and then concentrated under vacuum to a volume of 4 L to produce (5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (XXIII) (3.9 Kg, 8.3 mol, 82.3% purity, 100% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 4.70 (d, J=6 Hz, 2H), 5.49 (t, J=6 Hz, 1H), 7.19 (d, J=7.2 Hz, 5H), 7.20-7.35 (m, 10H), 8.31 (d, J=2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H); ESIMS found C26H20BrN3O m/z 492.0 (M+Na).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH2:14][OH:15])=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](O)(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])=[O:10])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)O
Reactant: C[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1C[C@H]1C(=O)N[C@H]1CC[C@H](C)CC1
Temperature: 0 °C

Procedure:
Add, dropwise, to a stirring suspension at −20° C. of trans-2-hydroxymethyl-cyclopropanecarboxylic acid trans-(4-methylcyclohexyl)-amide (Example 11c) (2.85 g, 13.5 mmol), triethylamine (3.74 mL, 27.0 mmol) and 4-(dimethylamino)pyridine (0.1 g, 0.82 mmol) in dichloromethane (100 ml) a solution of methanesulfonic acid (1.59 mL, 20.3 mmol) in DCM (10 mL). When the reaction is complete, pour the mixture into ice water and extract the mixture with DCM. Combine the extracts, wash with 0.1N KHSO4, brine, dry over MgSO4 and concentrate under vacuum. Treat the residue with a mixture of isopropanol/heptane and collect the precipitate by filtration to obtain 2.91 g (74%) of solid, MS m/z=290 (M+H)+.
Reaction SMILES: F[C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=[CH2:12])[C:4]=2[CH:3]=1.[CH3:16][O-:17].[Na+].O>CO>[CH3:16][O:17][C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=[CH2:12])[C:4]=2[CH:3]=1
Reactant: C=CCn1c(=O)cnc2ncc(F)cc21
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCn1c(=O)cnc2ncc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 407.4 %

Procedure:
A solution of 7-fluoro-1-(2-propen-1-yl)pyrido[2,3-b]pyrazin-2(1H)-one (196 mg, 0.956 mmol) in MeOH (5 ml) was treated with sodium methoxide (25% w/v in MeOH, 1.03 ml. 4.780 mmol) and stirred at rt for 1 h. The reaction was repeated with more 7-fluoro-1-(2-propen-1-yl)pyrido[2,3-b]pyrazin-2(1H)-one (657 mg, 3.204 mmol) in MeOH (15 ml) and sodium methoxide (25% w/v in MeOH, 3.45 ml. 16.02 mmol). This reaction was also stirred for 1 h after which time both reaction mixtures were combined and treated with water (100 ml). The mixture was then extracted with DCM (3×100 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow solid which was purified by column chromatography on silica with ethyl acetate to give the desired product as a brown solid (846 mg, 94%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16]1>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:19]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[O:20])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Cl)C1CCC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)C2CCC2)C1

Procedure:
Acylation of (R)-piperidin-3-yl-carbamic acid tert-butyl ester (300 mg) with cyclobutyl carbonylchloride (0.342 ml) was performed according to the method described for example 20c. The residue was concentrated in vacuo and used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:3]=1.[NH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[C:19]([CH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])=[CH:18]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[F:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:17]([NH:16][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[N:5][CH:6]=1)=[O:10])[CH:18]=[C:19]2[CH2:27][CH2:28][C:29]([OH:31])([CH3:30])[CH3:32]
Reactant: CC(C)(O)CCc1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2nccs2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2nccs2)ncc1C(=O)Nn1cc(CCC(C)(C)O)c2cc(F)ccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
A solution of 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (300 mg, 1.36 mmol) and 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (325 mg, 1.38 mmol) in DMF (5 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (380 mg, 1.38 mmol) and stirred at 50° C. for 2 h. The mixture is diluted with saturated aqueous Na2CO3 (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-7% MeOH in DCM to afford 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid [5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide (155 mg, 26%). MS: 440 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.14 (d, 1H), 8.08 (d, 1H), 7.40 (m, 3H), 7.06 (m, 1H), 4.31 (s, OH, 1H), 2.76 (s, 3H), 2.71 (m, 2H), 1.77 (m, 2H), 1.20 (s, 6H). IC50=5 nM.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[C:5]([C:18]([O:20]CC)=[O:19])[CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[C:5]([C:18]([OH:20])=[O:19])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)sc1Nc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc(C(=O)O)c(Nc2ccccc2[N+](=O)[O-])s1

Procedure:
Ethyl 5-ethyl-2-(2-nitroanilino)-thiophene-3-carboxylate (6.0 g) dissolved in ethanol (100 ml) and water (50 ml) and heated to 60° C. with stirring. Sodium hydroxide (5 N, 50 ml) was then added and the temperature maintained for 16 hours. The reaction mixture was cooled and diluted with water (500 ml), and solid title product filtered off, m.p. 189°-191° C. (EtOAc).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1>>[C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:15]([F:14])([F:25])[F:26])=[CH:17][CH:18]=3)=[O:24])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(-c2ccccc2)cs1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Product: O=C(C=Cc1cc(-c2ccccc2)cs1)c1ccc(C(F)(F)F)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-phenylthiophene-2-carbaldehyde and p-(trifluoromethyl)acetophenone, 3-(4-phenylthiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one was obtained as yellow solid.