Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17](O)=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].[OH:23][C:24]1([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:27][NH:26][CH2:25]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17]([N:26]2[CH2:27][C:24]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([OH:23])[CH2:25]2)=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16]
Reactant: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)N1CCCCC1C1(O)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1C1(O)CN(C(=O)c2cn3ccnc3c(Cl)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.3 %

Procedure:
A solution of 8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (78 mg, 0.18 mmol) (prepared using procedures similar to those described in US 2006030610 and US 2005054701), 1,1-dimethylethyl 2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate (46.7 mg, 0.18 mmol), 4-(dimethylamino)pyridine (66 mg, 0.55 mmol), and finally 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg, 0.21 mmol) in dimethylformamide (2 mL) was stirred at room temperature for 15 hours. The reaction mixture was partition between 5% aqueous lithium chloride and ethyl acetate and the aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with 1 N HCl, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by column chromatography. Eluting with ethyl acetate, the isolated product was concentrated in vacuo to afford 101 mg, 0.15 mmol (83%) of 1,1-dimethylethyl 2-[1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate as a white solid. The solid was immediately dissolved in methanol (5 mL) and 4 N HCl in dioxane was added. The solution was briefly heated to reflux and then was concentrated in vacuo. The resultant residue was purified by preparative reverse phase HPLC. Isolated product was concentrated in vacuo to afford 36 mg, 0.06 mmol (40%) of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol acetate as a white solid. 1H NMR (400 MHz, DMSO): 8.78 (s, 1H), 8.19 (s, 0.5H), 8.15 (s, 0.5H), 8.00 (s, 1H), 7.62 (s, 1H), 7.55 (d, 1H), 7.31 (d, 1H), 6.54-6.49 (m, 1H), 4.24-4.12 (m, 1H), 3.97-3.86 (m, 2H), 3.63-3.56 (m, 1H), 2.98-2.90 (m, 1H), 2.50-2.40 (m, 1H), 1.72-1.61 (m, 1H), 1.56-1.43 (m, 2H), 1.32-1.14 (m, 2H), 1.07-0.94 (m, 1H); MS (EI) for C22H22ClFI5O2: 570 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:6]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][CH2:3][C:4]1[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:6]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(COC)cc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 95.3 %

Procedure:
Ethyl ester (147) (20 mg, 0.046 mmol) was saponified with 1 N NaOH in THF and EtOH to give 18 mg (93%) of the title compound (148) as an off-white solid. mp 76-79° C. 1H NMR (400 MHz, CDCl3): δ 3.33 (s, 3H), 4.31 (s, 2H), 6.22 (d, J=15.9 Hz, 1H), 6.60 (d, J=8.8 Hz, 2H), 7.15-7.20 (m, 2H), 7.20-7.30 (m, 5H), 7.44 (t, J=7.9 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.95 (s, 1H). LCMS (ESI): m/z 433 (M+Na)+, m/z 409 (M−H)−. HRMS (EI) Calc for C27H22O4: 411.1596 (M+•). Found: 411.1606.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])([O:12][CH2:13][CH3:14])=[O:11].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: CC(=O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccccc1N=C(C)c1ccccc1

Procedure:
A solution of acetophenone (100 ml), o-carbethoxyaniline (90 ml), benzene (100 ml) was refluxed in the presence of molecular sieve (40 g) with continuous removal of water. N-(α-methyl benzylidene)-o-carbethoxyaniline (XV) was obtained by fractional distillation. XV had a boiling point of 123° at 0.1 millimeter.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=2)=[CH:4][CH:3]=1.[NH2:28][CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:28][CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])[N:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc12
Reactant: CC(C)(CN)CO
Solvent: CC#N
Product: Cc1nccn2c(-c3ccnc(NCC(C)(C)CO)n3)c(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 16.7 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methylimidazo[1,2-a]pyrazine (1.50 g, 391 mmol) in ACN (30 mL) was added 3-amino-2,2-dimethyl-1-propanol (Lancaster, 2.0 g, 20 mmol). The reaction mixture was heated to about 80° C. After about 1.5 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure. The resulting crude material was purified by silica gel chromatography with DCM/MeOH/NH4OH (step-wise gradient, 990:9:1 then 980:18:2) to give an oil after concentration. The oil was dissolved in a minimum amount of DCM and heptane was added until a white precipitate formed. The suspension was concentrated under reduced pressure. The resulting solid was triturated with heptane and filtered to give the title compound (1.36 g, 86%): LC/MS (Table 1, Method g) Rt=2.41 min; MS m/z: 407.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2
Reactant: COc1cc(O)ccc1-c1nc2ncccc2[nH]1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Oc1ccc(-c2nc3ncccc3[nH]2)c(OC)c1

Procedure:
Prepared analogously to Example 1 from 2-(2'-methoxy-4'-hydroxy-phenyl)-imidazo[4,5-b]pyridine and ethanesulfonic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:14]([NH2:16])=O>O>[CH2:12]([C:4]1[S:3][C:2]2[N:1]=[CH:14][N:16]=[C:7]([OH:8])[C:6]=2[CH:5]=1)[CH3:13]
Reactant: NC=O
Reactant: CCOC(=O)c1cc(CC)sc1N
Solvent: O
Product: CCc1cc2c(O)ncnc2s1
Yield: 57 %

Procedure:
A solution of ethyl 2-amino-5-ethylthiophene-3-carboxylate (5 g, 25.09 mmol, 1.00 equiv) in formamide (60 mL) was stirred for 4 h at 180° C. in an oil bath. The reaction mixture was cooled and diluted with 200 mL of water. The solids were collected by filtration and dried in an oven under reduced pressure to give 2.6 g (57%) of 6-ethylthieno[2,3-d]pyrimidin-4-ol as a black solid. MS: m/z 181 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH:6]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1B(O)O.[F-].[Cs+]>C(COC)OC>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:22]2[CH:21]=[CH:20][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
Tetrakis triphenyphosphine palladium (65 mg, 7.4 mol %) was added to a dimethoxy ethane (5.4 mL) solution of (4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester (447 mg, 1.5 mmol), 2-naphthaleneboronic acid (286 mg, 1.67 mmol) and cesium fluoride (505 mg, 3.33 mmol). The reaction was flushed with nitrogen and heated in an oil bath to 100° C. while stirring for 3 hours. The reaction was then diluted with ethyl acetate and extracted with water, 1 M sodium hydroxide, water and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with 5% ethyl acetate in hexanes to give the title compound as a clear oil (273 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.01-7.38 (m, 11H), 3.72 (s, 3H), 3.69 (2H)
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:29][CH:30]=[CH:31][C:24]=34)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].O.[OH-].[Li+]>CO.O>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:29][CH:30]=[CH:31][C:24]=34)[CH:20]=[N:19]2)[CH2:5][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH2:7]1)#[N:2]
Reactant: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2cnc(C(=O)O)cn2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylate (0.15 g, 0.36 mmol) and lithium hydroxide monohydrate (46 mg, 1.1 mmol) in methanol (3 mL) and water (1 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to afford the desired product (quantitative) which was directly used in the next step reaction without further purification.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[CH3:28][C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:32]3[CH2:33][CH2:34][C:29]([OH:35])([CH3:28])[CH2:30][CH2:31]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CC1(O)CCNCC1
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCC(C)(O)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with 4-methyl-piperidin-4-ol in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 408 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].B.O1CCCC1>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(CO)cc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
A solution of 3-methyl-4,5-dinitrobenzoic acid (4.0 g, 17.7 mmol) in tetrahydrofuran (200 mL) was cooled to −70° C. with a dry ice/acetone bath. To this solution was added borane-tetrahydrofuran (1M in tetrahydrofuran, 35.4 mL). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 16 h. The reaction was incomplete, was again cooled to −50° C. and additional borane-tetrahydrofuran (1M in tetrahydrofuran, 35.4 mL) was added. Again, the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction was quenched with a mixture of acetic acid and water (1:1, 30 mL) while cooling at 0° C. After stirring for 30 min, all organic solvent was evaporated and the aqueous material was neutralized by pouring into ice cold saturated sodium bicarbonate (350 mL) in small portions. The aqueous layer was extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was subjected to flash column chromatography (1:2 hexanes/ethyl acetate) to give the title compound (3.2 g, 86% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.00(s, 1H), 7.62 (s, 1H), 4.82 (s, 2H), 2.41 (s, 3H). 13C-NMR (CDCl3, 75 MHz) δ 144.5, 143.3, 140.9, 134.3, 132.9, 120.8, 63.0, 17.4.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Cl:15][C:16]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[Cl:15][C:16]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(Cl)c1OC
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3Cl)nc2n(CC)c1=O
Yield: 53.6 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.00 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.94 g (12.1 mmol) of 2-chloro-3,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from 2-propanol/water to give 2.19 g (yield 54%) of Compound 105 as pale yellow needles.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].[O-]CC.[Na+].Br[CH2:16][C:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=O>C(O)C>[CH2:2]([O:4][C:5]([C:6]1[CH:16]=[C:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[NH:9][C:7]=1[NH2:8])=[O:10])[CH3:3]
Reactant: CCOC(=O)CC(=N)N
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(C#N)cc2)[nH]c1N
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
A mixture of 42.53 g (0.255 mol) carbamimidoyl-acetic acid ethyl ester hydrochloride in 70 ml absolute ethanol is treated at 0 to 5° C. with 95.3 ml of a 21% sodium ethoxide solution in ethanol (0.255 mol) and stirred 5 min at 0 to 5° C. 4-Bromoacetyl-benzonitrile (28.6 g, 0.128 mol) is then added in portions over 20 min at 0 to 5° C. Stirring is continued at this temperature for 5 min then the ice bath is removed and the yellow suspension is stirred over night at RT. The solid is filtered off, washed with ethanol and ether and re-suspended in 450 ml actonitrile. The mixture is heated for 5 min under reflux, filtered while still hot and then cooled in an ice bath. The title compound is collected by succion and dried. Flash chromatography (dichloromethane/ethyl acetate mixture) of the mother liquors gives an additional crop of the title compound as a yellow solid; m.p. 228-229° C.; MS-ES+: (M+H)+=254.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH3:12][O:13][CH2:14][CH2:15]Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[NH:10])[N:7]([CH2:15][CH2:14][O:13][CH3:12])[C:6]=2[CH:11]=1
Reactant: COCCBr
Reactant: Nc1nc2cc(F)ccc2s1
Product: COCCn1c(=N)sc2ccc(F)cc21

Procedure:
Commercially available 5-fluoro-benzothiazol-2-ylamine and 2-bromoethyl methyl ether were processed as described for Example 46A to afford the title compound. MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CCOCC>[C:15]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a mixture of phenylalanine (500 g, 3.03 mol), 2N aqueous sodium hydroxide solution (4 L) and ether (500 mL) was added dropwise benzoyl chloride (455 mL, 3.93 mol) under ice-cooling over about 55 min. The resulting mixture was stirred at room temperature for 16 h, cooled with ice and acidified with conc. hydrochloric acid to pH 2. The precipitated crystals were extracted with ethyl acetate. The obtained extracts were combined and washed with water, dried over anhydrous sodium sulfate and concentrated to ca. 2 L. Then hexane was added to the resulting suspension. The resulting precipitate was collected by filtration to give 815 g (100%) of N-benzoylphenylalanine.
Reaction SMILES: [NH2:1][C:2]1[C:24]([C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:5]2[N:6]=[CH:7][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[CH2:34][CH2:35][O:36][CH2:37][CH2:38]Cl>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:8]1[CH:7]=[N:6][C:5]2[N:4]([N:3]=[C:2]([N:1]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:24]=2[C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Reactant: ClCCOCCCl
Product: O=C(NC1CCCC1)c1c(N2CCOCC2)nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc12
Yield: 33 %

Procedure:
The compound obtained in Example 40 and 2-chloroethylether were treated in the same manner as described in Example 43 to obtain 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-morpholino-3-(N-cyclopentylcarbamoyl)pyrazolo[1,5-a]pyrimidine (23 mg, yield: 33%) as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:7]=1.C(N(C(C)C)CC)(C)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:7]=1)[NH:8][CH2:9][CH2:10][CH2:11][O:12][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCCNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-((5-bromo-2-nitrophenyl)amino)propan-1-ol (6.73 g, 24.45 mmol) was dissolved in dry dichloromethane (50 mL), and diisopropylethyl amine (6.41 mL, 36.7 mmol) and tert-butyldimethylsilyl chloride (4.42 g, 29.3 mmol) were added. This mixture was stirred at room temperature for 3 h. The organic layer was washed with water, then saturated aqueous ammonium chloride, and then brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give crude 5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-nitroaniline as an orange oil which was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:16](O)=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[C:23]([F:26])([F:25])[F:24])[CH2:3][CH2:2]1.Cl.[F:28][C:29]1([F:33])[CH2:32][NH:31][CH2:30]1>>[F:28][C:29]1([F:33])[CH2:32][N:31]([C:16]([C:15]([NH:14][C:12]([C:10]2[CH:9]=[CH:8][C:7]([C:23]([F:24])([F:26])[F:25])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:13])([CH2:19][CH3:20])[CH2:21][CH3:22])=[O:17])[CH2:30]1
Reactant: FC1(F)CNC1
Reactant: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)O
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)N1CC(F)(F)C1

Procedure:
In analogy to the procedure described in Example 293, 2-[(6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid (Example 252 b) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) were condensed to the title product. MS (EI): m/e=450.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][N:5]=[CH:4][N:3]=1.[SH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:8][C:7]1[C:2]([S:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: Clc1ncncc1Br
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1ncncc1Br
Temperature: 150 °C
Yield: 83.6 %

Procedure:
A mixture of 4-chloro-5-bromopyrimidine (0.193 g, 1.0 mmol), methyl 2-mercaptoacetate (0.116 g, 1.1 mmol) and sodium carbonate (0.159 g, 1.5 mmol) in DMF (0.7 mL) was heated under microwave irradiation to 150° C. for 20 minutes. The mixture was washed with water, extracted with ethyl acetate and purified by chromatography to yield methyl 2-(5-bromopyrimidin-4-ylthio)acetate (0.22 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)=[O:4].C([O-])(=O)C.[K+].Br[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1)[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(Br)cc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: Fc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc2ccc(-c3ccc(F)cn3)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Bromo-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid methyl ester (202.0 mg, 0.495 mmol), dichlorobis(triphenylphosphine)palladium (II) (35.6 mg, 0.051 mmol), bis(pinacol)diborane (189.3 mg, 0.745 mmol), potassium acetate (147.3 mg, 1.51 mmol), and dioxane (1.6 ml) were mixed. The air was replaced three times with argon under reduced pressure. The mixture was microwaved at 120° C. for 30 minutes. Dichlorobis(triphenylphosphine)palladium (II) (35.6 mg, 0.051 mmol) and 2-bromo-5-fluoro-pyridine (206.9 mg, 1.48 mmol) were added to the reaction mixture. After deaeration, the air was replaced three times with argon. This was heated and stirred at 100° C. for three hours. The reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by amino gel column chromatography (n-hexane/ethyl acetate=7/100 to 63/100). Thus, 6-(5-fluoro-pyridin-2-yl)-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid methyl ester was obtained as a pale yellow amorphous material (150.5 mg, yield of 72%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[OH:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>C1(C)C=CC=CC=1>[NH2:26]/[C:4](/[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[F:1])=[C:6]1\[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[S:10]\1
Reactant: N
Reactant: O=C(c1ccccc1F)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1F
Yield: 50 %

Procedure:
Prepared as in Example 1 from 2-(2-fluorobenzoyl)benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia, but using a mixture of toluene and petroleum ether in a volume ratio of 2:1 in place of pure toluene, giving a yield of 50% of theory. Yellow crystals; m.p. 156°-158° C. (ethyl acetate/petroleum ether 1:1).