Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[C:42]2[N:43]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:44](=[O:48])[CH2:45][CH2:46][CH2:47][C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[C:42]3[N:43]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:56])[CH3:55])[C:44](=[O:48])[CH2:45][CH2:46][CH2:47][C:41]=3[CH:40]=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: C[Si](C)(C)CCOCN1C(=O)CCCc2cccc(CCl)c21
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)CCC3)cc1

Procedure:
Analogously to Method D, 0.400 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.303 g of 9-chloromethyl-1-(2-trimethylsilanylethoxymethyl)-1,3,4,5-tetrahydrobenz[b]azepin-2-one are reacted. The title compound is obtained as a yellowish oil. Rf=0.20 (1:1 EtOAc-heptane); Rt=6.58.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[C:4]([N:11]=[CH:12][N:13]([CH3:15])[CH3:14])[N:3]=1.[C:16](OC(OCC)OCC)(=O)C>>[CH3:15][N:13]([CH:12]=[N:11][C:4]1[N:3]=[C:2]2[N:1]=[CH:10][N:9]([CH3:16])[C:7](=[S:8])[N:6]2[N:5]=1)[CH3:14]
Reactant: CNC(=S)n1nc(N=CN(C)C)nc1N
Reactant: CCOC(OCC)OC(C)=O
Product: CN(C)C=Nc1nc2ncn(C)c(=S)n2n1
Yield: 56 %

Procedure:
The synthesis method of Example 55 was applied. The compound (486 mg) obtained in Example 33 and diethoxymethyl acetate (5 ml) were used as reagents. The mixture was reacted at 95° C. for 2 hours to give 282 mg of pale-brown crystals (yield 56%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][N:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:11])[CH:10]=[C:5]2[NH:4][N:3]=1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN1CCCC1=O.CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:6]3=[N:7]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-n2nc3c(N)n[nH]c3cc2=O)cc1
Reactant: Clc1ncccn1
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(-n2nc3c(Nc4ncccn4)n[nH]c3cc2=O)cc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 56.6 %

Procedure:
To 3-amino-5-(4-methoxy-phenyl)-1,5-dihydro-pyrazolo[4,3-c]pyridazin-6-one (purchased from Bionet, 67.6 mg, 0.2628 mmoles) in N-methylpyrrolidinone (263 uL) was added 2-chloro-pyrimidine (15.1 mg, 0.5 eq). The reaction was stirred for 5 hours at 130° C. to give crude desired product as evidenced by mass spectrometry. The reaction was diluted with methanol (2 ml) and purified by reverse phase chromatography to give 25 mg (28%) of pure 5-(4-methoxy-phenyl)-3-(pyrimidin-2-ylamino)-1,5-dihydro-pyrazolo[4,3-c]pyridazin-6-one (I-17) as a solid. LC/MS: tret=2.13 min, M+H−=336.1.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11](OS(C(F)(F)F)(=O)=O)=[C:10]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:10]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[C:9]1=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Solvent: C1CCOC1
Product: Cc1cc(-c2c(N3CCCCC3)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 1-benzyl-6-chloro-3-(3-methyl-isoxazol-5-yl)-2-oxo-1,2-dihydro-quinolin-4-yl ester (25 mg, 0.050 mmol) in 1 ml of THF was added piperidine (17 mg, 0.20 mmol). The mixture was stirred at rt for 16 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20% EtOAc/hexanes) gave 21.0 mg (97%) of product as a yellow green oil: 1H-NMR (CDCl3; 400 MHz) δ 7.93 (d, 1H, J=2.6 Hz), 7.37 (dd, 1H, J=9.0, 2.3 Hz), 7.18-7.33 (m, 6H), 6.56 (s, 1H), 5.50 (s, 2H), 2.99 (m, 4H), 2.40 (s, 3H), 1.64-1.76 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H24ClN3O2, 434.2 (M+H), found 434.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1Cl.[CH3:14][CH:15]([SH:17])[CH3:16]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1[S:17][CH:15]([CH3:16])[CH3:14]
Reactant: CC(C)S
Reactant: COC(=O)c1ccc(OC)nc1Cl
Product: COC(=O)c1ccc(OC)nc1SC(C)C
Yield: 87 %

Procedure:
2-Chloro-6-methoxy-nicotinic acid methyl ester (52 mg, 0.26 mmol) obtained in Step B and isopropylthiol were reacted in the same manner as in Step B of Preparation Example 9 to obtain the title compound (54 mg, 87%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:18][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[O:20])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:25]([CH3:33])[CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:3]=1.[ClH:34].[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41].C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:34].[CH3:17][C:14]1([CH3:16])[C:13]2[CH2:12][CH2:11][N:10]([CH2:18][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[O:20])[CH2:9][C:8]=2[C:7]2[C:2]([O:1][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][N:36]([CH3:43])[CH3:35])=[CH:3][C:4]([CH:25]([CH3:33])[CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][C:6]=2[O:15]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Reactant: CN(C)CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN(C)C)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1

Procedure:
The above-titled compound was prepared according to the method of Example 8 by reacting equimolar quantities of {[10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridin-2-yl]acetyl}urea and 4-(dimethylamino)butyric acid hydrochloride in the presence of dicyclohexylcarbodiimide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])[CH:5]=[C:4]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[CH:3]=1.[Mg].Cl[P:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[P:33](Cl)Cl>C1COCC1>[CH3:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]1[CH:7]=[C:2]([P:26]([C:2]2[CH:3]=[C:4]([C:16]3[C:17]([CH3:23])=[CH:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:5]=[C:6]([C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[CH:12][C:13]=3[CH3:14])[CH:7]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[P:33]([C:2]2[CH:3]=[C:4]([C:16]3[C:17]([CH3:23])=[CH:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:5]=[C:6]([C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[CH:12][C:13]=3[CH3:14])[CH:7]=2)[C:2]2[CH:3]=[C:4]([C:16]3[C:17]([CH3:23])=[CH:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:5]=[C:6]([C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[CH:12][C:13]=3[CH3:14])[CH:7]=2)[CH:3]=[C:4]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[CH:5]=1
Reactant: Cc1cccc(C)c1-c1cc(Br)cc(-c2c(C)cccc2C)c1
Reactant: ClP(Cl)c1ccccc1P(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cc(-c2c(C)cccc2C)cc(P(c2cc(-c3c(C)cccc3C)cc(-c3c(C)cccc3C)c2)c2ccccc2P(c2cc(-c3c(C)cccc3C)cc(-c3c(C)cccc3C)c2)c2cc(-c3c(C)cccc3C)cc(-c3c(C)cccc3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromo-3,5-bis(2,6-dimethylphenyl)benzene (2.74 g, 7.50 mmol) was added dropwise to magnesium (0.28 g, 11.52 mmol) and THF (10 mL) in an argon atmosphere. After the dropwise addition, the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to ambient temperature and filtered, and the thus-obtained THF solution of 1-(3,5-bis(2,6-dimethylphenyl))magnesium bromide, and 1,2-bis(dichlorophosphino)benzene (0.28 g, 1.00 mmol) were reacted as in Production Example 1. The reaction was allowed to proceed overnight at 60° C. After purification, the title compound was obtained as a yellow powder (0.70 g, yield 62%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][S-:13].[Na+]>CO.O>[Br:1][C:2]1[N:3]=[C:4]([S:13][CH3:12])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1nc(Br)cn2ccnc12
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a stirred suspension of 489 g (1766 mmol) 6,8-dibromo-imidazo[1,2-a]pyrazine which was prepared according to a procedure described in the Journal of Medicinal Chemistry, 1984, vol. 27, #2, p. 206-212 in 2.9 L methanol at −20° C. was dropwise added a solution of 225 g sodium methanethiolate in 800 mL water. After stirring overnight, the clear solution was poured into 30 L water, the precipitate was filtered, washed with water and dried in vaccuo to yield 301 g (70%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:17])[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14]C)[CH:10]=[CH:9][C:8]=2[CH3:16])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].CO>ClC1C=CC=CC=1>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH3:16])=[C:7]2[C:12]=1[CH:13]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:17])[NH:6]2
Reactant: COc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CO
Product: Cc1ccc(O)c2cc(C(C)C)c(=O)[nH]c12
Temperature: 110 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
3-Isopropyl-5-methoxy-8-methylcarbostyril (2.10 g, 9.90 mmol) was suspended in chlorobenzene (50 ml), to which aluminum chloride (4.20 g, 31.5 mmol) was added. The mixture was stirred at 110° C. for 1 hour. The reaction mixture was cooled on ice, and methanol (30 ml) was added thereto. After stirring for 10 minutes, the reaction mixture was condensed under reduced pressure. The resultant residue was recrystallized from water to obtain 1.60 g of the title compound as pale yellow powdery crystals (81.1%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[NH:14][C:13](=[O:22])[C:12]([C:23]([O:25]CC)=[O:24])=[CH:11]3)[CH:7]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>C(OCC)(=O)C>[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[NH:14][C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]3)[CH:7]=1)=[O:37]
Reactant: O=C=Nc1ccccc1Br
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c(C(F)(F)F)cc2[nH]c1=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Br)OCc1cn(-c2cc3cc(C(=O)O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 38.1 %

Procedure:
To a suspension of the compound of Example 17 (100 mg, 262 μmol) in ethyl acetate (3 ml) was added 2-bromophenyl isocyanate (104 mg, 524 μmol), and the mixture was refluxed for 24 hours. After cooling, the precipitated crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure. These were suspended into ethanol (3 ml), 1 mol/L aqueous solution of lithium hydroxide (903 μl) and successively water (3 ml) were added, and the mixture was stirred for 75 minutes at 50° C. Ice water was added to the reaction mixture, the insolubles were filtered off. then the pH value was brought to 4 with 3 mol/L hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and then dried under reduced pressure, thereby obtaining 55.0 mg of title compound as colorless powder. Yield 34%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.[Li]C(C)(C)C.C(=O)=O.[C:20](OC)(=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1COCC1.CCOC(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:25]
Reactant: Cn1ccc2cccc(Br)c21
Reactant: COC(=O)C(=O)OC
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cccc2ccn(C)c12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
A solution of 1-methyl-7-bromoindole (1.53 g, 7.29 mmol) in THF (50 mL) was cooled to −78° C. and a 1.7 M solution of tBuLi in pentanes (10 mL, 17 mmol) added dropwise over 10 min. After 15 min, the resultant bright yellow suspension was transferred over 15 min via a cannula cooled with dry ice to a solution of dimethyl oxalate (2.13 g., 18.1 mmol) in THF (40 mL) maintained at −78° C. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The cloudy yellow mixture was treated with pH 7.0 buffer, poured into EtOAc and the EtOAc washed with pH 7.0 buffer, saturated aq NaHCO3, brine, dried (MgSO4) and concentrated to a cloudy oil. Flash chromatography (10% EtOAc/hexanes) afforded the title compound (896 mg, 57%) as a bright yellow oil. 1H NMR (400 MHz, DMSO-d6) 7.97 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz, 1H), 7.48 (d, J=3 Hz, 1H), 7.20 (dd, J=8 Hz, 1H), 6.66 (d, J=3 Hz, 1H), 3.95 (s, 3H), 3.79 (s, 3H). 13C (75.5 MHz, DMSO-d6) 185.80, 164.31, 133.64, 133.02, 131.23, 128.07, 127.04, 118.77, 118.25, 102.15, 53.01, 37.49. IR (CHCl3, cm−1) 1739, 1678. Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.48; H, 5.23; N, 6.51.
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])[N:5]=1)C.[C:13]([O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH2:20])([CH3:16])([CH3:15])[CH3:14]>C(O)C>[C:13]([O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH:20][C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])[N:5]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC1=NS(=O)N=C1OCC
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CCO
Product: CCOC1=NS(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Yield: 882.3 %

Procedure:
A solution of 3,4-diethoxy-1-oxo-1,2,5-thiadiazole (1 g, 0.52 mmol) and L-tyrosine t-butyl ester (1.25 g, 0.52 mmol) in ethanol (25 mL) was stirred at room temperature for 60 hr. Solvent was removed under reduced pressure and the residue purified by flash column chromatography (silica, hexane:EtOAc 1:1 to give N-(4-ethoxy-1-oxo-1,2,5-thiadiazol-3-yl)-L-tyrosine tert-butyl ester (1.75 g, 88%). MS (+ESI, m/e) 382 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[CH:5]([CH:6]([OH:11])[CH2:7][CH2:8][CH:9]=2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14].[CH2:16]([O:18][CH2:19]Cl)[CH3:17]>C([N-]C(C)C)(C)C.[Li+]>[CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([CH:6]([O:11][CH2:19][O:18][CH2:16][CH3:17])[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14]
Reactant: CCOCCl
Reactant: CC1C(C)(C)C2=CCCC(O)C2C1(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOCOC1CCCC2C1C(C)(C)C(C)C2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A reaction flask was charged with 100 mL of lithium diisopropyl amide (LDA, available from Aldrich Chemical Company) (2M in heptane/THF) and cooled to 0° C. 1,1,2,3,3-Pentamethyl-tetrahydro-4-indanol, as described in U.S. Pat. No. 3,636,165, 40 g (0.19 mole) was added in portions to the LDA solution. The reaction was aged 30 minutes then 18.5 g (0.2 mole) of ethoxy methyl chloride was added to the reaction mass at 0° C. The mass was allowed to exotherm to 25° C. The reaction was quenched with 100 g of 10% aqueous sodium carbonate. The mass was transferred to a separatory funnel and water washed. The organic layer was distilled. The procedure afforded a 60% yield (30 g) of 1,1,2,3,3-pentamethyl-hexahydro-4-(ethoxymethoxy)-1H-indene.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH:17]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:14][C:11]2=[N:12][CH:13]=1)(C)(C)C.[Cl:35]CCl>Cl>[ClH:35].[CH:19]1([CH2:18][CH:17]([C:15]2[NH:14][C:11]3=[N:12][CH:13]=[C:8]([NH2:7])[CH:9]=[C:10]3[CH:16]=2)[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)Nc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(N)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (584 mg, 1.21 mmol) in dichloromethane (20 mL) was bubbled in dry hydrogen chloride gas for 30 min. The resulting mixture was stirred for 3 h at room temperature. The solvent was removed to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-ylamine hydrochloride salt (508 mg, 100%) which was used in the next step without purification: LC/MS m/e calcd for C21H25N3O2S [M+H]+ 384.52, observed 384.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1cccc(Br)c1
Product: N#Cc1cccc(-c2cc([N+](=O)[O-])ccc2F)c1

Procedure:
3-Bromobenzonitrile and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane were coupled using the procedure described in Example 7 part c) to afford 2′-fluoro-5′-nitrobiphenyl-3-carbonitrile as a brown solid: δH (360 MHz, DMSO) 7.33-7.40 (2H, m), 7.46-7.55 (2H, m), 7.61 (1H, ddd, J 8, 8 and 2), 7.96-8.01 (1H, m), 8.61 (1H, dd, J 5 and 2), 8.77 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([F:37])[CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([F:37])[CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-2-(3-fluoro-4-methoxyphenyl)-6-(3-(piperazin-1-yl)propoxy)-1H-inden-1-one (70 mg, 1.2 eq, 0.1 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (47%).
Reaction SMILES: [Na+].[F:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[F:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1F
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1F)NC(=O)CN2
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A mixture of N-(4-fluoro-5-methyl-2-nitrophenyl)glycine sodium salt (0.125 g, 0.548 mmol) and tin (II) chloride dihydrate (0.370 g, 1.64 mmol, Aldrich, used as received) in ethanol (3.0 mL) was refluxed for 30 min. It was then cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water (4.0 mL) and basified with saturated NaHCO3 to pH ~8. The resulting suspension was extracted with ethyl acetate (30 mL). The extract was dried over Na2SO4 and evaporated to yield 0.032 g of the title compound as a yellow powder, which was used for the next reaction; 1H NMR (DMSO-d6): 2.024 (s, 3H), 3.607 (s, 2H), 5.751 (s, 1H), 6.453 (d, 1H, J=9.9 Hz), 6.456 (d, 1H, J=8.1 Hz), 10.162 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
To a stirred solution of 4-methoxyphenol (75 mg, 0.60 mmol) and 4-chloro-quinazoline (125 mg, 76 mmol) in 3 mL of DMF was added sodium hydride (60% oil suspension, 30 mg, 0.75 mmol) at 0° C., then the reaction mixture was allowed to warm to room temperature and stirred for 5 h. The reaction was quenched by adding 50 uL of water and diluted with 25 mL of ethyl acetate. It was washed with water (25 mL×3), saturated NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by chromatography (25% ethyl acetate/hexanes) to give the title compound (134 mg, 0.53 mmol, 89%). 1H NMR (CDCl3): 8.78 (s, 1H), 8.38 (m, 1H), 7.89-8.02 (m, 2H), 7.67 (m, 1H), 7.19 (m, 1H), 7.00 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:15][C@H:16]([C:21]([O:23]C)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11].[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:15][C@H:16]([C:21]([OH:23])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]([N:12]([CH3:13])[CH3:14])=[O:11]
Reactant: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(C(=O)N(C)C)c1ccc(F)cc1F)C(=O)O
Reaction time: 4 h
Yield: 98.1 %

Procedure:
To a solution of methyl N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (101 mg) in methanol (3 ml) was added a solution of lithium hydroxide (15.4 mg) in water (1 ml). After stirring vigorously for 4 hours the solvent was removed in vacuo. The residue was diluted with water (10 ml) then neutralised with 2N hydrochloric acid. This solution was applied to an Oasis™ cartridge (6 g) and eluted with water (x2) and methanol (x2). The required fractions were combined and evaporated to afford N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (95 mg).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3Br)[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.[CH3:35][C:36]1(C)C(C)(C)OB(C=C)O1>O>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3[CH:35]=[CH2:36])[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccn1
Solvent: O
Product: C=Cc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(C)C)c3)cn2CCN2CCC2)CC1

Procedure:
a mixture of 6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine (70.00 mg; 0.13 mmol; 1.00 eq.), 4,4,5,5-Tetramethyl-2-vinyl-[1,3,2]dioxaborolane (0.03 ml; 0.16 mmol; 1.20 eq.), (4.77 mg; 0.01 mmol; 0.07 eq.) and in doxane 15 ml and water 1.5 ml, stirred at 50 C for overnight.