Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH3:19])[C:17]=1[OH:18])=[O:12])[CH3:9].[OH-].[Na+]>O>[CH3:5][O:18][C:17]1[C:16]([CH3:19])=[CH:15][NH:14][C:13]=1[C:11]([O:10][CH2:8][CH3:9])=[O:12]
Reactant: CCOC(=O)c1[nH]cc(C)c1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1[nH]cc(C)c1OC
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Add dimethyl sulfate (3 mL, 3.99 g, 31.63 mmoles) to a mixture of 3-hydroxy-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (3.5 g, 20.69 mmoles) and 2M sodium hydroxide (75 mL, 1500 mmoles) and stir the reaction mixture vigorously for 30 mins at room temp (water cooling bath applied). Collect the resultant precipitate and wash with water. Add more dimethyl sulfate (3 mL, 3.99 g, 31.63 mmoles) to the filtrate and stir for 30 minutes. Collect the resultant precipitate and wash with water. Add more dimethyl sulfate (3 mL, 3.99 g, 31.63 mmoles) to the filtrate and stir for 1 h. Combine the isolated precipitates and dry in a vacuum oven at 50° C. for 30 minutes to give ethyl 3-methoxy-4-methyl-1H-pyrrole-2-carboxylate (3.221 g, 84.98% yield). MS (m/z): 184.09 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25](OCC)=[O:26])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[OH:11])=[O:5])[CH3:2].[C:31]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([N:17]2[C:18](=[O:30])[C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]2=[O:26])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[O:11][CH3:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccccc1C(=O)Nn1cc(C(=O)OCC)c(O)c1C(=O)OCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(N2C(=O)c3ccccc3C2=O)c(C(=O)OCC)c1OC
Temperature: 50 °C
Yield: 75.1 %

Procedure:
A mixture of 393C (0.84 g, 2 mmol) and K2CO3 (1.0 g, 7.25 mmol) in acetone (5 ml) was heated at 50° C. for 30 min, then cooled to rt. Dimethyl sulfate (0.29 ml, 3.0 mmol) was added, the resulting mixture was heated at 40° C. until starting material consumed, quenched with brine and extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by silica gel flash column chromatography to afford 393D (0.58 g, 74% for 3 steps from 393B) (0%-5% EtOAc—CH2Cl2).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:15]1([CH2:21]O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.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.O>[CH2:21]([O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccnc(-n2nccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
To a solution of 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile (186 mg, 1 mmol), phenylmethan-1-ol (216 mg, 2 mmol), and PPh3 (523 mg, 2 mmol) in THF (10 mL) was added dropwise DIAD (402 mg, 2 mmoL) at 0° C. under N2. Then the mixture was stirred at rt overnight. Water was added, and the reaction mixture was extracted with EtOAc, then washed with water and brine. The organic phase was dried, concentrated, and purified by prep-HPLC to afford the title compound (60 mg). 1H NMR (400 MHz, CDCl3): δ 5.25 (2H, s), 5.75 (1H, d, J=2.0 Hz), 7.36-7.44 (5H, m), 7.57 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.71 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H12N4O, 277. Found, 277.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:2].[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].O1C2(CCNCC2C2C=CC(C=C3SC(=S)NC3=O)=CC=2)OCC1>>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[C:24]2[S:18][C:19](=[S:20])[NH:21][C:22]2=[O:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(COc1ccc(C=O)cc1)OCC
Reactant: O=C1CSC(=S)N1
Agent: O=C1NC(=S)SC1=Cc1ccc(C2CNCCC23OCCO3)cc1
Product: CCOC(COc1ccc(C=C2SC(=S)NC2=O)cc1)OCC

Procedure:
Under nitrogen, a mixture of 4-hydroxybenzaldehyde (1.71 g, 14 mmol), bromoacetaldehyde diethyl acetate (37.4 g, 190 mmol), tetrabutylammonium bromide (0.61 g, 1.9 mmol) and potassium carbonate (26.1 g, 190 mmol) in 100 mL of toluene was refluxed for 2.5 days. After cooling the mixture was dissolved in water and extracted with dichloromethane. The organic layers were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (eluent: hexanes/ethyl acetate) to give 4-(2,2-diethoxyethoxy) benzaldehyde as a colorless oil (2.60 g, 79%). The title compound was prepared from 4-(2,2-diethoxyethoxy) benzaldehyde and rhodanine according to the procedure of Intermediate 15 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.14(t, J=7.1 Hz, 6 H), 3.50-3.80 (m, 4 H), 4.04(d, J=5.0 Hz, 2 H), 4.05-4.30(m, 2 H), 6.06 (t, J=5.0 Hz, 1 H), 7.14 (d, J=9.0 Hz, 2 H), 7.60 (d, J=9.0 Hz, 2 H), 7.63(s, 1 H); MS (ES) m/z:351.7 ((M−H)−, 100%); HRMS Calcd. for C16H20NO4S2 (MH+): 353.0775. Found: 353.0757.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:8]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1cccc(-c2ccncc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a solution of 3-(pyridin-4-yl)benzoic acid (300 mg, 1.5 mmol) in DCM (6 mL) was added EDCI (430 mg, 2.20 mmol), HOBt (296 mg, 2.20 mmol), Et3N (556 mg, 4.50 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (370 mg, 1.80 mmol). The mixture was stirred at room temperature for 16 h, then the reaction mixture was washed with water and extracted with DCM. The organic layer was then dried, concentrated and the residue purified by prep-HPLC to give the title product (230 mg, Yield 40%). 1H NMR (400 MHz, MeOD) δ 8.54 (d, J=4.0 Hz, 2H), 8.16 (s, 1H), 7.85-7.80 (m, 2H), 7.64 (dd J=4.0 Hz, 2H), 7.48 (dd, J=7.6 Hz, 1H), 7.03-6.95 (m, 4H), 4.13 (br.s, 1H), 3.66 (s, 2H), 3.60-3.48 (m, 2H), 2.80-2.77 (m, 4H), 2.63-2.59 (m, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([N:14]([CH3:13])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:6]
Reactant: COC(C(=O)O)c1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: COC(C(=O)N(C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1)c1ccccc1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from methoxy(phenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 407.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].N1C=CC=CC=1.[Br:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][Br:16]
Reactant: O=C(Cl)CCCBr
Reactant: COC(=O)[C@@H](N)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)CCCBr)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 1.08 g (8.4 mmole) of L-valine methyl ester in 30 ml of CH2Cl2 was added 1.36 ml (16.8 mmole) of pyridine, cooled to 0° C. and 1.55 g (8.4 mmole) of 4-bromobutanoyl chloride added. The solution was stirred at 0° C. for 40 minutes and at RT for 1 h. The solution was washed with satd. NaHCO3, brine and dried with anhy. Na2SO4; filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (5% EtOAc/CH2Cl2) to provide 1.82 g (77%) of desired product. 300 MHz 1H NMR (CDCl3) δ 0.92 (d, J=6 Hz, 3H), 0.96 (d, J=6 Hz, 3H) 2.20 (m, 3H), 2.46 (m, 2H), 3.50 (m, 2H), 3.76 (s, 3H), 4.58 (dd, J=4,7 Hz, 1H), 5.97 (br d, J=7 Hz, 1H). Mass spectrum: (M+H)+=297.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[OH:22]>C(OCC)C.N1C=CC=CC=1>[C:1]([O:22][C:15]1[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=1[Cl:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
A solution of decanoyl chloride (Pfaltz and Bauer, 5.6 ml) and 2,4,5-trichlorophenol (5.6 g) in diethyl ether (1 L) and pyridine (120 ml) is stirred for 4 hours. The reaction mixture is filtered and dried in vacuo. The 2,4,5-trichlorophenyl n-decanoate is purified on a silica-gel column (Woelm), using toluene as the eluent. Fractions are monitored by TLC, using short-wave UV for detection. Appropriate fractions are pooled and dried in vacuo to give 10.4 g of 2,4,5-trichlorophenyl n-decanoate.
Reaction SMILES: [H][H].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17](=[N:25]O)[C:16]=4[CH:15]=[CH:14][CH:13]=3)[NH:9][C:8]=2[CH:27]=1>C(O)C.O1CCCC1.[Ni]>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]([NH2:25])[C:16]=4[CH:15]=[CH:14][CH:13]=3)[NH:9][C:8]=2[CH:27]=1
Reactant: Cc1ccc2nc(-c3cccc4c3-c3ccccc3C4=NO)[nH]c2c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc2nc(-c3cccc4c3-c3ccccc3C4N)[nH]c2c1
Temperature: 60 °C
Yield: 75.2 %

Procedure:
The procedure used in Example 6 is followed. In a 100 ml autoclave, dissolve 1 g of 4-(6-methyl-1H-benzimidazol-2-yl)-9H-fluoren -9-one oxime (Z,E), obtained in the previous stage, in a mixture of 40 ml of ethanol and 40 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to an initial hydrogen pressure of 1 bar and heat the autoclave at 60° C. for 3 hours. After cooling, the volume of hydrogen absorbed is 142 ml. After filtration of the catalyst over Celite, the filtrate is concentrated under reduced pressure and then taken up in petroleum ether and filtered. In this way, we obtain 720 mg of 4-(6-methyl-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a beige solid, which is used as it is in the following stage, with the following characteristic:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[CH3:25][C:26]([CH3:28])=O.C([BH3-])#N.[Na+]>Cl.C(O)C>[Br:19][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]3[C:20]([Cl:23])=[CH:21][CH:22]=[C:4]([NH:3][CH:26]([CH3:28])[CH3:25])[C:5]=3[Cl:24])[C:10]2=[N:17][C:16]=1[CH3:18]
Reactant: CC(C)=O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(OCc3c(Cl)ccc(NC(C)C)c3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (100 mg) and acetone (116 mg) in 3M HCl solution in ethanol (2 ml) was added sodium cyanoborohydride (25 mg) in one portion. The mixture was stirred for 2 hours at ambient temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried and concentrated in vacuo to give an oil, which was purified by preparative thin-layer chromatography on silica gel (ethyl acetate:n-hexane =1:2, V/V), to give 3-bromo-8-(2,6-dichloro-3-isopropylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine as a white solid (50 mg).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.O=P(Cl)(Cl)Cl.[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:9]1[C:4]2[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnc2cnc(F)cc12
Reactant: Nc1cccc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Yield: 63 %

Procedure:
Reaction of 6-fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (0.60 g, 3.6 mmol) with POCl3, followed by reaction of the crude 4,6-dihalo compound with 3-bromoaniline gives 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (0.73 g, 63%). 1H NMR (DMSO) δ 10.09 (1H, brs), 8.96 (1H, s), 8.75 (1H, s), 8.25 (2H, m), 7.90 (1H, brd, J=6.5 Hz), 7.44 -7.34 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1B1OC(C)(C)C(C)(C)O1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)=[N:32][CH:31]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[O:34][C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=4)=[N:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(Nc2ncc(-c3ccc(Br)cc3)o2)c1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Temperature: 100 °C

Procedure:
Preparation of -(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester has been described [Tet. Lett. 41-(19), 3705-3708, 2000]. The boronate ester (1.1 g, 3.6 mmol, 1.5 equiv) and [5-(4-bromo-phenyl)-oxazol-2-yl]-(3-chloro-phenyl)-amine (0.84 g, 2.4 mmol, 1.0 equiv) were dissolved in 12 mL DME and then charged with 3 mL of a 2M Na2CO3 solution. Pd(Ph3)4 on polystyrene resin (0.72 g, 0.072 mmol) was added, and the suspension was sparged with nitrogen for 10 min, then heated to 100° C. overnight. The reaction was then filtered to remove catalyst, and following solvent removal the product was triturated with hexanes and ether to afford the title compound: (M+H)+452.1.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][CH:16]=2)[C:3]([OH:26])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 108.7 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-propionic acid methyl ester (575 mg, 1.62 mmol) in methanol (10 mL) and water (10 mL) was treated with lithium hydroxide (778 mg, 18.5 mmol). The reaction mixture was stirred at 25° C. for 5 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (40 mL). This solution was acidified to pH=5 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×40 mL). The combined organic extracts were then washed with a half-saturated aqueous sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-propionic acid (601 mg, quant.) as a light brown oil: EI-HRMS m/e calcd for C21H27NO3 (M+) 341.1990, found 341.1996.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:32]=[CH:31][NH:30][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:32]=[CH:31][NH:30][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:25][CH2:26][N:27]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:28][CH2:29]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: CS(=O)(=O)Cl
Reactant: c1cc2c(Nc3ccc4cn[nH]c4c3)nc(Nc3ccc(N4CCNCC4)cc3)nc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4cc[nH]c4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
To a suspension of N4-(1H-indazol-6-yl)-N2-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (9 mg, 0.021 mmol) and triethylamine (TEA) (0.010 mL, 0.072 mmol) in CH2Cl2 (1 mL) at room temperature, methanesulfonyl chloride (MeSO2Cl) (0.006 mL, 0.077 mmol) was added. After being stirred at room temperature for 3 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give N4-(1H-indazol-6-yl)-N2-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (2 mg), MS 504.3 (M+H) (Compound 8-1); and N4-(1-(methylsulfonyl)-1H-indazol-6-yl)-N2-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (1 mg), MS 582.4 (M+H) (Compound 8-2).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]([C:16]4[CH:17]=[N:18][NH:19][CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:28])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH:41]1[CH2:46][CH2:45][S:44](=[O:48])(=[O:47])[CH2:43][CH2:42]1>C(OCC)(=O)C>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]([C:16]4[CH:20]=[N:19][N:18]([CH:42]5[CH2:41][CH2:46][CH2:45][S:44](=[O:48])(=[O:47])[CH2:43]5)[CH:17]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:28])=[O:5])[CH2:2][CH2:3]1
Reactant: C[C@H]1CCc2c(ccc(-c3cn[nH]c3)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: O=S1(=O)CCC(Br)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CCc2c(ccc(-c3cnn(C4CCCS(=O)(=O)C4)c3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 100-mL, round-bottom flask was charged with (S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.200 g, 0.56 mmol), cesium carbonate (0.114 g, 0.35 mmol), N,N-dimethylformamide (5 mL), and 4-bromo-1λ6-thiane-1,1-dione (0.114 g, 0.53 mmol). The resulting mixture stirred at 100° C. for 4 h and was then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (3×10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 25-50% ethyl acetate/petroleum). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, Water and acetonitrile (55% to 75% acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded 3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ6-thiane-1,1-dione (0.122 g, 43%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.76-0.82 (m, 1H), 0.92-1.02 (m, 2H), 1.13-1.22 (m, 4H), 1.42-1.50 (m, 1H), 1.95-2.08 (m, 3H), 2.08-2.13 (m, 1H), 2.14-2.37 (m, 3H), 2.68-2.77 (m, 1H), 3.11-3.19 (m, 2H), 3.37 (s, 1H), 3.53-3.60 (m, 1H), 4.66-4.72 (m, 1H), 4.74-4.81 (m, 1H), 6.79 (d, J=8.00 Hz, 2H), 6.98 (t, J=7.60 Hz, 1H), 7.23 (t, J=7.60 Hz, 2H), 7.62 (d, J=8.40 Hz, 1H), 7.83 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 506 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CS(C)(=O)=O
Product: CCOC(=O)C(=CN(C)C)S(C)(=O)=O
Temperature: 85 °C

Procedure:
6.65 g (40 mmol) of ethyl methanesulphonylacetate and 5.72 g (48 mmol) of N,N-dimethylformamide dimethyl acetal are admixed and heated at 85° C. overnight. The solution is concentrated using a rotary evaporator, and the solid is comminuted with cyclohexane and filtered off with suction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:18])[CH:7]=[CH:6]2
Reactant: COc1ccc2ncccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2[nH]c(=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-methoxyquinoline (2.08 g) in CHCl3 (45 mL) at r.t. was added m-chloroperoxybenzoic acid (3.38 g) portionwise over 10 min. After 30 min., CHCl3 (50 mL) was added and the solution washed with saturated aq. NaHCO3 (3×), dried (MgSO4) and concentrated. A portion of this material (500 mg) in DMF (10 mL) was treated with trifluoroacetic anhydride (TFAA) and stirred at r.t. for 17 hr. The TFAA was removed under vacuum and to the resulting solution was added water (60 mL). The mixture was extracted with EtOAc (6×) and the combined organics were dried (MgSO4) and concentrated. Trituration of the resulting material with acetone provided the title compound as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH:18]([CH:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=3)[CH3:30])[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][N:16]([C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:17][CH:18]2[CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=2)[CH3:30])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCNCC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a stirred solution of 4-[(3RS,4SR)-3-[(SR)-1-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-piperidine-1-carboxylic acid tert-butyl ester (0.28 g, 0.50 mmol) in 24 mL of CH2Cl2 was added 6 mL of TFA. After one hour at RT, the reaction was quenched by addition of aq. NaOH 1M (until ph=10) and the product was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo to yield 0.237 g (99%) of the title compound as a white foam. ES-MS m/e: 473.0 (M+H+).