Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(C)CNc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)CN(c1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixture of 1.70 g (0.0082 mole) of (rac)-2-methyl-3-phenylamino-propanoic acid ethyl ester, 1.7 g (0.0088 mole) of 2,4-dichloro-5-nitro-pyrimidine and 60 mL of ethyl acetate, was added 4.24 mL (0.0246 mole) of N,N-diisopropylethylamine. The mixture was stirred at room temperature for 2 hours, and then washed with successively with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (80:20) to give 2.99 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-phenyl-amino]-2-methyl-propanoic acid ethyl ester (IV-51) as yellow oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH3:10][CH:11]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:12][C:13]#[CH:14].C(N(CC)CC)C>C(OCC)C>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH:11]([CH3:10])[CH2:12][C:13]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:14]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#CCC(C)OC1CCCCO1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1cc(CC(C)OC2CCCCO2)on1

Procedure:
Ethyl chlorooximidoacetate (1 g, 6.60 mmol) and 2-(pent-4-yn-2-yloxy)tetrahydro-2H-pyran (3.33 g, 19.80 mmol) were dissolved in diethyl ether (20 ml) and the mixture was stirred vigorously. Triethylamine (0.920 ml, 6.60 mmol) diluted with diethyl ether was added dropwise. The reaction mixture was extracted with water and the organic phase dried with MgSO4, filtered and evaporated. The product was used in the next step without further purifications. LC-MS: [M+1]=284.32.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10](O)[CH3:11].S(Cl)([Cl:15])=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([Cl:15])[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1nc2ccccc2s1
Solvent: ClCCl
Product: CC(Cl)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-benzothiazolyl)ethanol (2.5 g) prepared according to J. Indian Chem. Soc., 566 (1974) in methylene chloride (50 ml) was added thionyl chloride (3.32 g) and the resulting solution stirred at room temperature for 1 hour. The solution was poured onto ice-water (100 ml) and the organic extract separated. This extract was washed with aqueous bicarbonate (10 ml of a 5% solution) and then with water (50 ml). The methylene chloride layer was dried over anhydrous magnesium sulfate and evaporated to a light yellow oil (2.08 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:39][CH3:40])=[C:16]([C:18]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=2[NH:30][C:31](=[O:38])[CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:19])[CH:17]=1>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:39][CH3:40])=[C:16]([C:18]2([OH:19])[C:20]3[C:21](=[CH:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=3)[NH:30][C:31](=[O:38])[CH:32]2[CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:17]=1
Reactant: COC(=O)CCC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)c1cc(Cl)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CC1C(=O)Nc2ccc(C(F)(F)F)cc2C1(O)c1cc(Cl)ccc1OC
Temperature: -78 °C
Yield: 100.3 %

Procedure:
A solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 57 mL, 28.5 mmol) was added to a stirred cold (−78° C.) solution of 4-[[2-[(5-chloro-2-methoxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]amino]-4-oxobutanoic acid, methyl ester prepared in Step A (4.05 g, 9.1 mmol) in anhydrous THF (25 mL) and maintained at −78° C. for 3 hours. Acidic work-up with 1N HCl and followed by extraction with EtOAc afforded the crude title compound (4.05 g, 100%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[C:33]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([C:37]1[CH:42]=[CH:41][C:40]([C:25]2[C:26]([CH3:28])=[CH:27][C:22]([S:21][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:9][CH:10]=3)[CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[CH:23][C:24]=2[CH3:30])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(SC(CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 367 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS: 570.2 [M−H]−; Isomer 2 MS: 570.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)CCl)[CH:2]=[CH2:3].[OH:13][C:14]1C=C(C=CC=1)C=O.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:7][C:6]=1[CH:14]=[O:13])[CH:2]=[CH2:3]
Reactant: O=Cc1cccc(O)c1
Reactant: C=CCOc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C=CCBr
Product: C=CCOc1ccccc1C=O
Reaction time: 18 h

Procedure:
c:- (A) 3-Allyloxybenzyl chloride was obtained as follows: A mixture of 3-hydroxybenzaldehyde (6 g), allyl bromide (6.25 g), and potassium carbonate (8.82 g) in DENT (30 ml) was stirred for 18 hours, poured into water (100 ml) and extracted with diethyl ether (3×150 ml). The combined organic extracts were washed with water (2×150 ml) and brine (2×150 ml), dried (magnesium sulphate) filtered and evaporated to give 2-allyloxybenzaldehyde (7.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]=1[N+:27]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Rh]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[NH2:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=Cc2ccccc2OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Rh]
Solvent: CCO
Product: Nc1cc(C(=O)O)ccc1CCc1ccccc1OCc1ccccc1

Procedure:
A mixture of methyl 4-[2-(2-benzyloxyphenyl)ethenyl)-3-nitrobenzoate (2.5 g) and 5% Rhodium on alumina (520 mg) in ethanol (200 ml) was stirred under 1 atm. of hydrogen for 20 hours. The mixture was filtered and the solvent evaporated. The residue was purified by subjecting to chromatography using ethylacetate: dichloromethane (9:1) as eluant. There was thus obtained methyl 4-[2-(2-benzyloxyphenyl)ethyl]-3-aminobenzoate (1.71 g).
Reaction SMILES: O/[C:2](/[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:3](/[C:10]#[N:11])\[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].O=P(Cl)(Cl)Cl.C([N:24](CC)CC)C>C(Cl)Cl>[NH2:24]/[C:2](/[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:3](/[C:10]#[N:11])\[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCN(CC)CC
Reactant: CCC(CC)/C(O)=C(\C#N)C(=O)OC(C)C
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(CC)/C(N)=C(\C#N)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
24.4 g (0.11 mol) of isopropyl (2Z)-3-hydroxy-2-cyano-4-ethyl-2-hexenoate were dissolved in CH2Cl2 and, at 25° C., 33.2 g (0.22 mol) of POCl3 were added. After cooling to 0° C., 43.8 g (0.44 mol) of triethylamine were added dropwise, and the mixture was stirred at 25° C. for 2 h. The solution was then concentrated and the residue was taken up in acetonitrile and cooled to 0° C., and 30 g (0.44 mol) of a 25 percent strength solution of ammonia were added dropwise. After 2 h of stirring, the mixture was concentrated to dryness, the residue was taken up in MTBE (methyl tert-butyl ether) and the organic phase was washed with NaOH and water, dried and concentrated. Purification by customary methods gave 10 g (40% of theory) of the title compound as a colorless solid (m.p. 140° C.).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH3:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][CH:4]=2)=[O:7])[CH2:13][CH2:12]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CN1CCN(C(=O)c2ccc(O)cc2)CC1
Product: CN1CCN(C(=O)c2ccc(OC(=O)N(C)c3ccccc3)cc2)CC1

Procedure:
The title product was prepared from 1-(4-hydroxybenzoyl)-4-methyl-piperazine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (22%, colorless oil). HPLC-MS: m/z=354.1 (M+1); Rt: 2.07 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@@:28]4([CH3:35])[CH2:32][O:31]C(C)(C)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:36]>CCO>[ClH:36].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@@:28]([OH:29])([CH3:35])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@]2(C)COC(C)(C)O2)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@](C)(O)CO)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
(S)—N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine (55 mg, 0.108 mmol) was dissolved in EtOH (3 mL). 1M HCl (0.3 mL) was added and the mixture was stirred at ambient temperature for 24 hours. Additional 1M HCl (0.3 mL) was added and the mixture was stirred overnight. The mixture was partitioned between saturated aqueous sodium bicarbonate and CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (15% methanol in EtOAc) to afford (S)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol hydrochloride (34.9 mg, 0.0691 mmol, 63.9% yield) as a white solid after HCl salt formation. Mass Spectrum (apci) m/z=451.1(M+H−H2O—HCl) (100) and 469.1 (M+H−HCl) (30).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].Cl.O1CCOCC1>C(O)(C)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4c5ccccc5C[C@@H]4O)n3)cc2CC1
Yield: 17.4 %

Procedure:
(1R,2S)-1-(2,5-Dichloro-pyrimidin-4-ylamino)-indan-2-ol (78 mg, 0.26 mmol) was dissolved in isopropanol (3 mL) and the solution was treated with 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (50 mg, 0.26 mmol) and 4N HCl/Dioxane (0.66 mL, 0.26 mmol). The reaction was then irradiated at 130° C. for a total of 30 minutes. The reaction mixture was reduced en vacuo and the crude product was isolated and purified by prep HPLC to afford 20.3 mg of (1R,2S)-1-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-indan-2-ol as an off-white solid. LC/MS (ESI)=450.26 (M+H), MP=209.1° C. 1H NMR (400 MHz, DMSO, d6) δ 9.41 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.40 (m, 1H), 7.29 (s, 1H), 7.26 (m, 2H), 7.13 (m, 1H), 7.03 (m, 1H), 6.59 (m, 1H), 3.62 (m, 4H), 3.40 (m, 2H), 3.25 (m, 3H), 2.90 (m, 3H), 2.37 (d, 2H, J=5.55 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[O:32]1[C:40]2[CH:39]=[CH:38][N:37]=[C:36]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[C:35]=2[CH:34]=[CH:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:44]4[CH2:45][CH2:46][N:41]([C:36]5[C:35]6[CH:34]=[CH:33][O:32][C:40]=6[CH:39]=[CH:38][N:37]=5)[CH2:42][CH2:43]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1cc2occc2c(N2CCNCC2)n1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2nccc3occc23)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-furo[3,2-c]pyridinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=633.99 (M+H+); retention time=0.64 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[H-].[Na+].[F:28][C:29]1[CH:30]=[CH:31][C:32]2[S:36][C:35](S(C)=O)=[N:34][C:33]=2[CH:40]=1>CN(C=O)C.C(OCC)(=O)C>[CH:14]1([N:13]([CH:17]2[CH2:19][CH2:18]2)[C:11]([C:9]2[N:8]([CH2:20][CH3:21])[C:6]3=[N:7][C:2]([NH:1][C:35]4[S:36][C:32]5[CH:31]=[CH:30][C:29]([F:28])=[CH:40][C:33]=5[N:34]=4)=[C:3]4[N:24]=[CH:23][N:22]([CH3:25])[C:4]4=[C:5]3[CH:10]=2)=[O:12])[CH2:16][CH2:15]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: CS(=O)c1nc2cc(F)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc4cc(F)ccc4s3)nc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
To a solution of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 50 mg, 0.148 mmol) in DMF (1.5 mL) was added sodium hydride (17.73 mg, 0.443 mmol). After 20 min, 5-fluoro-2-(methylsulfinyl)benzo[d]thiazole (example 40B, 95 mg, 0.443 mmol) was added in one portion. The reaction mixture was stirred at room temperature. The reaction mixture was diluted with ethyl acetate and quenched with water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with 10% lithium chloride solution (2×), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography using an Isco 12 g column eluting with 0-5% MeOH/CH2Cl2 to provide N,N-dicyclopropyl-6-ethyl-4-(5-fluorobenzo[d]thiazol-2-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (13 mg, 17.07% yield).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:18]([Cl:19])=[CH:17][C:6]2[CH:7](Cl)[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[F:1][C:2]([F:21])([F:20])[C:3]1[C:18]([Cl:19])=[CH:17][C:6]2[CH:7]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1cc2c(cc1Cl)C(Cl)Cc1ccccc1S2
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2Cc3ccccc3Sc3cc(C(F)(F)F)c(Cl)cc32)CC1
Yield: 56 %

Procedure:
A mixture of 7-trifluoromethyl-8,10-dichloro-10,11-dihydrodibenzo(b,f)thiepine (2.89 g), 1-methylpiperazine (1.8 ml) and chloroform (2.5 ml) was refluxed for 7 hours. The chloroform was evaporated under diminished pressure, the residue dissolved in benzene (30 ml), washed with water, and the benzene layer separated and shaken with an excess of 3 N-HCl. The precipitated hydrochloride was filtered, added to the aqueous layer of the filtrate and the base liberated by addition of ammonium hydroxide. It was extracted with benzene and the conventional work-up procedure yielded 1.93 g (56%) of the crude 7-trifluoromethyl-8-chloro-10-(4-methylpiperazino)-10,11-dihydrodibenzo(b,f)thiepine. Neutralization with maleic acid in ethanol followed by addition of ether yielded the crystalline maleate which was crystallized from ethanol; m.p. 197°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][OH:23].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:21][CH2:22][OH:23])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1cc(S(=O)O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(S(=O)(=O)CCO)ccc1Cl

Procedure:
40 g of 4-Chloro-3-nitrobenzenesulfinic acid, 27.8 g of potassium carbonate, 24.8 g of 2-bromoethanol and 200 ml of dimethylformamide were mixed together and reacted at 50° C. for a period of 8 hours. The reaction mixture was then poured into of water and extracted with ethyl acetate. The organic layer was recovered and the solvent was removed by distillation under reduced pressure. The oily residue was refined using silica gel short-column chromatography to obtain an oily product.
Reaction SMILES: CC([CH2:4][C:5]([OH:7])=[O:6])=O.[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9]>>[C:5]([OH:7])(=[O:6])[CH3:4].[C:5]([OH:7])(=[O:6])[CH3:4].[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9]
Reactant: CC(=O)CC(=O)O
Agent: Oc1ccc(O)cc1
Product: CC(=O)O

Procedure:
The diacetate of hydroquinone had a tendency to sublime into the distillation column. It was, therefore, necessary to charge the reactor in such a way so as to make up for this loss of the diacetate of hydroquinone. The highest intrinsic viscosity was obtained when a 1.6% molar excess of hydroquinone diacetate was employed. Air was used to cool the condenser, since water cooling caused more sublimate to form in the condensation column. Excess sublimate in the distillation path would eventually inhibit the formation of high vacuum in the latter stages of the polymerization reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:26]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:26]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccc(-c4ccccc4)n3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3cccc(-c4ccccc4)n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(6-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (685 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(6-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (482 mg, yield: 75%). This was recrystallized from ethanol-hexane. Melting point: 95–96° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.O=P(Cl)(Cl)Cl.O.CN([CH:21]=[O:22])C>>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc(Br)c(C=O)c(OC)c1
Temperature: 100 °C
Yield: 65 %

Procedure:
A solution of 1-bromo-3,5-dimethoxybenzene (10.0 g, 46.1 mmol) in DMF (40 mL) was treated with POCl3 (6.32 mL, 69.1 mmol) at 0° C. and heated to 100° C. for 6 h. The reaction was cooled to room temperature and water (40 mL) was added. The resulting mixture was heated to 50° C. 1 h. The reaction was cooled down and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=2:1) to give the title compound (7.26 g, 65%). 1H NMR (300 MHz, CDCl3) δ 10.24 (s, 1H), 6.81 (s, 1H), 6.42 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][C:7]1[C:8]2[CH2:29][NH:28][CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:16][CH:15]=2)[N:12]=1.[CH2:33]=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][C:7]1[C:8]2[CH2:29][N:28]([CH3:33])[CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:18][CH:19]=2)[N:12]=1
Reactant: C=O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CCc4cccc(F)c4)n2)CNCC3)cc1
Product: Cc1nccn1-c1ccc(Nc2nc(CCc3cccc(F)c3)c3c(n2)CCN(C)C3)cc1
Yield: 4.7 %

Procedure:
4-(3-Fluorophenethyl)-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (5.92 mg, 4.7%, Example 49a) was synthesised from 4-(3-fluorophenethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 443.3 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:28])[CH:20]=[CH:21][C:22]4[S:23][CH:24]=[C:25]([Br:27])[CH:26]=4)[C@@H:15]([CH3:29])[C:14]3=[O:30])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.C([O-])(=O)C.[NH4+:42]>>[NH2:42][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:28])[CH:20]=[CH:21][C:22]4[S:23][CH:24]=[C:25]([Br:27])[CH:26]=4)[C@@H:15]([CH3:29])[C:14]3=[O:30])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: C[C@H]1C(=O)N(Cc2ccc3c(Cl)ccnc3c2)CCN1C(=O)C=Cc1cc(Br)cs1
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Product: C[C@H]1C(=O)N(Cc2ccc3c(N)ccnc3c2)CCN1C(=O)C=Cc1cc(Br)cs1
Temperature: 120 °C
Yield: 62.2 %

Procedure:
(S)-1-(4-Chloroquinolin-7-ylmethyl)-4-[3-(4-bromothiophen-2-yl)acryloyl]-3-methyl piperazin-2-one (0.50 g, 0.9 mmol) is treated with phenol (˜2 g) and ammonium acetate (0.5 g, 6.4 mmol) and heated to 120° C. in a sealed vessel for 1 hour. Upon cooling, the solution is partitioned between 2 N NaOH and ethyl acetate. The organic layer is separated and washed with fresh 2 N NaOH (3×100 mL) and water. The organic layer is concentrated and the residue is purified by reverse phase HPLC (gradient elution of 10% of 0.1% aqueous TFA/acetonitrile to 100% acetonitrile) to give the title compound (0.22 g, 0.56 mmol). MS m/z: [M+H]+=485, 487, Cl pattern. 1H NMR (CD3OD, 300 MHz) δ8.2-8.4 (m, 2H), 7.7-7.8 (m, 2H), 7.6 (d, 1H), 7.5 (s, 1H), 7.3 (s, 1H), 6.9-7.0 (m, 1H), 6.7 (d, 1H), 5.0-5.1 (m, 1H), 4.9 (q, 2H), 4.3-4.4 (m, 1H), 3.5-3.7 (m, 2H), 3.3-3.4 (m, 2H), 1.5 (d, 3H).