Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cnc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
At room temperature, to a solution of 189h (90 mg, 0.13 mmol) in i-propanol/THF (1:1, 5 mL) and water (0.5 mL) was added lithium hydroxide (126 mg, 2.9 mmol). The reaction mixture was stirred at 35° C. for 0.5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified with by reverse-phase prep-HPLC to afford 189 (60 mg, 71%) as yellow solid. MS-ESI: [M+H]+ 638.3. 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J=5.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J=1.5 Hz, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 6.89 (s, 1H), 5.04-5.01 (m, 1H), 4.72-4.50 (m, 6H), 4.32-4.30 (m, 1H), 4.15-4.09 (m, 2H), 3.88-3.86 (m, 1H), 3.72 (s, 3H), 3.57-3.49 (m, 5H), 2.61-2.43 (m, 8H), 1.92-1.78 (m, 4H).
Reaction SMILES: O=O.[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>>[Br:3][C:4]1[CH:5]=[C:6]([O:10][CH2:13][CH:12]=[CH2:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: O=O
Agent: [K+]
Product: C=CCOc1cccc(Br)c1

Procedure:
The compounds of this invention in which X is oxygen are available as in the foregoing, but using a 5-substituted 3-chromanone. This molecule can be produced by a sequence of reactions beginning with m-bromophenol. Briefly, m-bromophenol is treated with allyl bromide in the presence of potassium carbonate to produce allyl 3-bromophenyl ether. The ether is converted to 2-allyl-3-bromophenol upon heating it in the presence of N,N-dimethylaniline. The phenol, upon reaction with ethyl chloroacetate, is converted to the ethyl ester of 2-allyl-3-(carboxymethoxy)bromobenzene. Upon oxidation using ozone followed by reductive work up, the allyl group is converted to a formylmethyl substituent which is then further oxidized using Jones' Reagent to the carboxymethyl substituent, the resulting product being the ethyl ester of (2-carboxymethyl-3-bromo)phenoxyacetic acid. The carboxylic acid group of this compound is esterified with t-butyl acetate and concentrated H2SO4 to form the ethyl ester of 3-bromo-2-(carbo-t-butoxymethyl)phenoxyacetic acid. In the presence of potassium t-butoxide, the diester is cyclized to form 4-t-butoxy-carbonyl-5-bromo-3-chromanone. Upon stirring at room temperature in the presence of acid, the latter is converted to 5-bromo-3-chromanone.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[C:25]([N:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[CH:4][CH:3]=[N:2]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Oc1ccccc1-c1ccn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Oc1ccccc1-c1ccnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
A mixture of 2-(pyrazol-5-yl)phenol (Catalan, et al., J. Am. Chem. Soc., 114(13):5039-48, 1992, 10 mmol, 1.60 g), triethylamine (40.0 mmol, 5.6 ml), and acetonitrile (55 ml) is cooled in an ice bath under N2 and treated dropwise with chlorotrimethylsilane (12.0 mmol, 1.52 ml). After the addition is complete, the cold bath is removed and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture is then treated with trityl chloride (10.0 mmol, 2.78 g) and stirred at ambient temperature overnight, followed by refluxing for 1 hour. The reaction mixture is concentrated, treated with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3×50 ml). The extracts are dried over magnesium sulfate and concentrated to a viscous oil. The oil is crystallized from 20% ethyl acetate/hexane to give 1.72 g of N-trityl-2-(pyrazol-5-yl)phenol.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([CH3:16])=[C:9]([CH2:12][C:13]([CH3:15])=[CH2:14])[C:10]=1[CH3:11])=[O:5])C.[Li+].[OH-]>C(O)C>[CH3:11][C:10]1[C:9]([CH2:12][C:13]([CH3:15])=[CH2:14])=[C:8]([CH3:16])[S:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: C=C(C)Cc1c(C)sc(C(=O)OCC)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: C=C(C)Cc1c(C)sc(C(=O)O)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 3,5-dimethyl-4-(2-methyl-allyl)-thiophene-2-carboxylic acid ethyl ester (978 mg, 4.1 mmol) in ethanol (20 mL) is added 3M aq. LiOH (10 mL) and the mixture is stirred at 60° C. for 1 h. The mixture is partitioned between DCM (100 mL) and 1M aq. HCl (75 mL). The aq. phase is re-extracted with DCM (2×50 mL). The combined organic extracts are dried (MgSO4), filtered and evaporated to give 653 mg of 3,5-dimethyl-4-(2-methyl-allyl)-thiophene-2-carboxylic acid as a light yellow powder; LC-MS: tR=0.94 min, [M+1+CH3CN]+=252.04; 1H NMR (CDCl3): δ 11.50 (br. s, 1H), 4.75 (s, 1H), 4.39 (s, 1H), 3.17 (s, 2H), 2.42 (s, 3H), 2.37 (s, 3H), 1.75 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:54])([F:53])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[C:34]([O:46][CH3:47])=[N:35][CH:36]=[C:37]([C:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41])[CH:38]=4)=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=3)[C@H:21]2[CH3:52])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.Cl.[F:56][CH:57]1[CH2:60][NH:59][CH2:58]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C1COCC1>[F:8][C:9]([F:54])([F:53])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[C:34]([O:46][CH3:47])=[N:35][CH:36]=[C:37]([C:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41])[CH:38]=4)=[CH:31][N:30]=[C:29]([N:59]4[CH2:60][CH:57]([F:56])[CH2:58]4)[N:28]=3)[C@H:21]2[CH3:52])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1
Reactant: COc1ncc(C(C)(O)C(F)(F)F)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: FC1CNC1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ncc(C(C)(O)C(F)(F)F)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C

Procedure:
Triethylamine (0.218 mL, 1.566 mmol) was added to a mixture of THF (2 mL), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-{2-methoxy-5-[(2RS)-1,1,1-trifluoro-2-hydroxypropan-2-yl]pyridin-3-yl}-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Step B, 220 mg, 0.313 mmol) and 3-fluoroazetidine hydrochloride (105 mg, 0.939 mmol). The reaction was placed under nitrogen and heated to 60° C. for 45 minutes; LCMS showed complete conversion to product. The reaction was diluted with 20 mL ethyl acetate and poured into 20 mL 10% citric acid, The organic layer was washed with 30 mL brine, then dried over sodium sulfate and concentrated. Purification on an X-Bridge 21.2×150 mm RP column with sample loaded using 7:3:1 CH3CN/water/DMSO (3 mL) employed a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient at 15 mL/minutes over 20 minutes. The product of interest eluted in 70% portion of the above gradient. Rich cut of pure product peak was lyophilized to give product as a white solid. LCMS (M+H)+: 698.5. 1H NMR (500 MHz, CDCl3): 1:1 diasteromeric mixture: δ 8.38 (m, 1H), 8.26 (s, 0.5H), 8.24 (s, 0.5H), 7.91 (bs, 1H), 7.82 (m, 0.5H), 7.79 (d, J=2.2 Hz, 0.5H), 7.74 (s, 1H), 7.71 (s, 1H), 5.62 (d, J=8.4 Hz, 0.5H), 5.55 (m, 0.5H), 5.44 (m, 0.5H), 4.86 (m, 0.5H), 4.72 (d, J=16.5 Hz, 0.5H), 4.52 (m, 2.5H), 4.33 (m, 3H), 4.00 (s, 1.5H), 3.42 (bs, 0.5H), 3.28 (s, 0.5H), 3.99 (s, 1.5H), 1.85 (s, 3H), 0.77 (d, J=6.6 Hz, 1.5H), 0.73 (d, J=6.6 Hz, 1.5H). RTA IC50: 14 Nm.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][C@:20]2([F:28])[C:24]([O:26][CH3:27])=[O:25])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.C(Cl)Cl.CO.[Pd]>[F:28][C@:20]1([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22][CH2:23][C@H:19]1[NH:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)(=[O:16])=[O:17]
Reactant: COC(=O)[C@@]1(F)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@]1(F)CCC[C@H]1NS(=O)(=O)c1ccc(O)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of methyl (1R,2R)-2-({[4-(benzyloxy)phenyl]sulfonyl}amino)-1-fluorocyclopentanecarboxylate in EtOAc/CH2Cl2/MeOH (5 mL/2 mL/10 mL) was added 10% Pd/C (0.14 g). The reaction vessel was purged with nitrogen followed by hydrogen. The reaction was stirred for 1 h under 1 atmosphere of hydrogen, and then filtered through celite and concentrated to afford methyl (1R,2R)-1-fluoro-2-{[(4-hydroxyphenyl)sulfonyl]amino}cyclopentanecarboxylate as an amorphous solid (0.433 g, 97%). MS: 318.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:10]([N:23]([CH3:25])[CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:33][C:32]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[C:37]#[N:38])=[CH:31][C:30](=O)[O:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:13]([NH:14][C:30](=[O:29])[CH2:31][C:32]([C:34]2[CH:41]=[CH:40][CH:39]=[C:36]([C:37]#[N:38])[CH:35]=2)=[O:33])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:10]([N:23]([CH3:24])[CH3:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1-c1cccc(F)c1F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-c1cccc(F)c1F

Procedure:
The title compound was prepared from (5-amino-2-dimethylamino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example J3) 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as a yellow solid (145 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[C:6]3[N:23]=[C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=4)[N:21]=[CH:20][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[OH-].[Na+:39]>C(O)C>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[C:6]3[N:23]=[C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([O-:31])=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=4)[N:21]=[CH:20][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[Na+:39]
Reactant: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)[O-]

Procedure:
200 mg of 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl) -5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid was stirred in 4 mL of ethanol in a screw-top vial. 1.1 mol equivalents of sodium hydroxide solution (406 μL, 1.044 M in water) were added. The solid dissolved followed by formation of a yellow precipitate. The sample was a mixture of Form 4 and Form 24. The solid was washed with 10 mL of ethanol and 20 mL of diethyl ether, and dried under vacuum at 70° C. for 2 days, and at 60° C. for a further 3 days to give Form 24. XRPD data for Form 24 is shown in FIG. 17 and Table 7; DSC data is shown in FIG. 18; TGA data is shown in FIG. 19.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[C@@H:3]1[CH2:14][OH:15].[ClH:16].C[C@H]1CCN[C@@H]1CO>>[ClH:16].[OH:15][CH2:14][C@@H:3]1[C@@H:2]([OH:1])[CH2:6][CH2:5][NH:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Agent: C[C@H]1CCN[C@@H]1CO
Agent: Cl
Product: OC[C@H]1NCC[C@@H]1O

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2R, 3S)-3-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate using the methods used to prepare [(2S,3S)-3-methyl-2-pyrrolidinyl]methanol hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 1H), 2.0 (m, 1H), 2.5 (m, 2H), 3.2 (m, 2H), 3.3 (m, 1H), 3.5 (m, 1H), 3.6 (m, 1H), 4.1 (m, 1H), 8.7 (s, 1H), 9.5 (m, 1H). ES+=117.97.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:10]2[C:14]3[CH:15]=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:22])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([O:42][CH3:43])[CH:33]=1)=[O:31]>O>[CH:3]1([N:10]2[C:14]3[CH:15]=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=[CH:18][C:13]=3[N:12]([S:38]([C:35]3[CH:36]=[CH:37][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][C:34]=3[O:42][CH3:43])(=[O:40])=[O:39])[C:11]2=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCOc1ccc2[nH]c(=O)n(C3CCCCCC3)c2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)n(C1CCCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
0.095 g of sodium hydride as a 60% dispersion in oil is added to a mixture of 0.7 g of 3-cycloheptyl-5-ethoxy-1,3-dihydro-2H-benzimidazol-2-one and 50 ml of DMF and the mixture is stirred for 30 minutes at RT. 0.7 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred overnight at RT. The reaction mixture is poured into iced water and the precipitate formed is filtered off and washed with water to give 0.9 g of the expected product, which is used as such in the next step.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[C:18]([CH:20]([F:22])[F:21])[N:17]=[C:16](S(C)(=O)=O)[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[C:37]([C@@H:39]([NH2:41])[CH3:40])[O:36][N:35]=2)=[CH:30][CH:29]=1.C(N(C(C)C)C(C)C)C>CS(C)=O.C(Cl)Cl.O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[C:18]([CH:20]([F:22])[F:21])[N:17]=[C:16]([NH:41][C@H:39]([C:37]2[O:36][N:35]=[C:34]([C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)[N:38]=2)[CH3:40])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(C(F)F)nc(S(C)(=O)=O)n1
Reactant: C[C@H](N)c1nc(-c2ccc(Cl)cc2)no1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](Nc1nc(C(F)F)cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1nc(-c2ccc(Cl)cc2)no1
Temperature: 25 °C
Yield: 37 %

Procedure:
A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)oxazolidin-2-one (0.146 g, 0.371 mmol), (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (91 mg, 0.41 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.097 mL, 0.56 mmol, 1.5 equiv) in DMSO (2.0 mL) was heated at 85° C. for 18 h. The reaction was cooled to room temperature and diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with DCM (20 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20% to 60%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6-(difluoromethyl)pyrimidin-4-yl)oxazolidin-2-one as a yellow oily solid in 37% yield. MS m/z 537.2 (M+H)+; Rt-1.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].C([O:13][C:14]([C@@H:16]1[CH2:20][C@@H:19](OS(C)(=O)=O)[CH2:18][C@H:17]1[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:15])C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C@H:19]1[CH2:20][C@@H:16]([C:14]([OH:15])=[O:13])[C@H:17]([CH2:26][N:27]2[CH2:28][CH2:29][CH:30]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:31][CH2:32]2)[CH2:18]1
Reactant: Sc1ccccc1Cl
Reactant: CCOC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1CN1CCC(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@H](Sc2ccccc2Cl)C[C@H]1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.4 %

Procedure:
To a solution of 2-chlorobenzenethiol (141 mg) in tetrahydrofuran (2 mL) was added sodium hydride (dispersion in oil, 55% w/w, 50 mg). The mixture was stirred 20 min at room temperature. Then the mixture was cooled down to 0° C. and a solution of (1R,2R,4S)-2-[4-(4-Fluoro-phenyl)-piperidin-1-ylmethyl]-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 148 step 4, 180 mg) in tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was stirred at room temperature over 24 h then partitioned between hydrochloric acid (1N) and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with a saturated aqueous solution of sodium carbonate and brine then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (98:2 to 9:1 v/v) as eluant to afford the title compound (31 mg, 16%) as a light brown solid. MS (EI): 448.1 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH:10]2[C:15](=O)[CH2:14][CH2:13][O:12][CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:31][C:32]([NH2:34])=[NH:33])[CH:22]=[CH:23][C:24]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1.N1C=CC=NC=1>>[CH2:7]([C:8]1[C:10]2[CH2:11][O:12][CH2:13][CH2:14][C:15]=2[N:34]=[C:32]([NH:31][C:21]2[CH:22]=[CH:23][C:24]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:19]([O:18][CH3:17])[CH:20]=2)[N:33]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCOCC1C(=O)Cc1ccccc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: c1cncnc1
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)COCC3)ccc1-n1cnc(C)c1
Yield: 3.7 %

Procedure:
4-Benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (16.00 mg, 3.7%) was obtained from 3-(2-phenylacetyl)dihydro-2H-pyran-4(3H)-one and 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine by the general procedure for pyrimidine preparation.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].Cl.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][NH2:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C#N)nc1C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(CN)nc1C
Reaction time: 8 h

Procedure:
To a solution of compound 3 in Scheme 4-3 (58 mg, 0.44 mmol) in MeOH (5 mL) and 6N HCl (1 mL) was added Pd/C (10 mg) at room temperature, the mixture was filled with hydrogen for three times and stirred overnight. The reaction mixture was filtered through celite and washed with MeOH and the filtrate was concentrated. The residue was concentrated to give compound 4 as a dark brown solid.
Reaction SMILES: C(OCCCC)CCC.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][CH:12]=1.BrBr.[CH2:23]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH3:19][CH:18]([N:33]1[CH2:34][CH2:35][CH:30]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:31][CH2:32]1)[CH:17]([OH:20])[C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: c1ccc(Cc2ccncc2)cc1
Agent: BrBr
Solvent: CO
Solvent: CCCCOCCCC
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To 15 ml of di-n-butyl ether were added 6.0 g of 4'-hydroxypropiophenone. 6.6 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 10 minutes and then nitrogen was introduced thereinto at a flow rate of 200 ml/minute for one hour at room temperature. To the treaction liquid were then added 7.5 g of 4-benzylpyridine and 100 ml of methanol, and the mixture was refluxed under heating for 5 hours. After stopping the heating, the reaction mixture was treated in the same manner as described in Example 35, whereby 11.3 g (73.4%) of ifenprodil were obtained as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH:21]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:25][CH:24]=1)=O>>[C:17]([C@H:11]1[C@H:12]2[CH2:16][C@H:15]([CH:14]=[CH:13]2)[C@H:10]1[NH:9][C:6]1[C:5]([Cl:20])=[CH:4][N:3]=[C:2]2[NH:1][C:21]([C:23]3[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)=[N:8][C:7]=12)(=[O:18])[NH2:19]
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(OCC(=O)O)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 29 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (1 eq.) and 2-(4-Formylphenoxy)acetic acid (53) (1.1 eq) were reacted in an analogous manner as compound CCXXIII to yield the desired product (29%) as a white solid. NMR: δ (1H, 400 MHz, DMSO-d6): 1.37 (1H, d, J=8.4 Hz), 2.23 (1H, d, J=8.4 Hz), 2.62 (1H, d, J=7.6 Hz), 2.77 (1H, s), 2.88 (1H, s), 4.31 (2H, bs), 5.20 (1H, t, J=8.8 Hz), 6.34-6.41 (2H, m), 6.77 (1H, d, J=8.8 Hz), 6.95 (2H, d, J=8 Hz), 7.07 (1H, d, J=8.8 Hz), 7.20-7.25 (1H, m), 7.75 (1H, bs), 7.90 (1H, s), 8.02 (2H, d, J=8.0 Hz).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].S(OC)(O[CH3:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][O:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1sc2ncccc2c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1sc2ncccc2c1OC

Procedure:
995 mg of 3-hydroxy-2-methoxycarbonylthieno[2,3-b]pyridine (4.76 mmol, 1 eg.) is reflux heated for 4 hrs with 0.54 ml of dimethyl sulfate (5.71 mmol, 1.2 eq.) in 30 ml of acetone in the presence of 987 mg of potassium carbonate (7.14 mmol, 1.5 eq.). The insoluble is filtered, washed with acetone and vacuum evaporated.