Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]1N[N:24]=[CH:23][CH:22]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC(B(O)O)=[CH:35][CH:34]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]1[CH:22]=[CH:23][N:24]=[CH:35][CH:34]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc2nc(-c3ccn[nH]3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3ccncc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 3 h

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-4-yl)quinolin-6-yl)acetic acid (73) was prepared following the procedure used for (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic acid of Example 70 except that pyridin-4-ylboronic acid was used instead of 1H-pyrazol-5-ylboronic acid and in the final step the reaction was stirred for 3 hours.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].O.Cl>CO>[N:15]1([CH:12]2[CH2:13][C:14]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][CH2:11]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1cccc2c1CC(N1CCCCCC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2c1CC(N1CCCCCC1)CC2
Temperature: 75 °C

Procedure:
A mixture of 1.56 g 7-(1-Hexahydroazepinyl)-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester, 1.57 mL 12 N NaOH, 1.57 mL water in 10 mL methanol was refluxed (70-80° C.) overnight. TLC showed no starting material remaining. The mixture was neutralized with 6 N HCl to pH 5-6 and concentrated to dryness using toluene and methanol. A white solid was recovered and used crude.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)[CH2:3][CH2:2]1.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)=[CH:13][C:9]([C:10]([NH:31][CH2:30][C:28]3[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=3)=[O:12])=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)c(F)c2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC2CC2)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 6-(cyclopropylmethoxy)-5-(3,4-difluorophenyl)-nicotinic acid (example CD) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 455.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][C:4]([N:6]([CH2:31][CH2:32][CH3:33])[C:7]1[S:8][CH:9]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]=3[N:15]=[CH:16][N:17]=2)[N:11]=1)=[O:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][CH:2]([CH3:34])[CH2:3][C:4]([N:6]([CH2:31][CH2:32][CH3:33])[C:7]1[S:8][CH:9]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[N:11]=1)=[O:5]
Reactant: CCCN(C(=O)CC(C)C)c1nc(-c2ncnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCN(C(=O)CC(C)C)c1nc(-c2ncnc3[nH]ccc23)cs1
Temperature: 80 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
To 55 mg [0.11 mmol] of 3-Methyl-N-propyl-N-{4-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-thiazol-2-yl}-butyramide dissolved in 2 mL of dry THF was added 5 drops of a 1M tetra n-butylammonium fluoride solution in THF, the vial was capped and heated/stirred at 80° C. for 4 hours. Reaction determined to be complete via HPLC and reaction was cooled. The solvent was removed under an N2 stream and residue was partitioned between DCM and water. The organic layer was brined and dried with anhydrous sodium sulphate and the solvent removed under vacuum. The crude product was purified on C18 silica with water/acetonitrile/TFA as the eluent, isolating 15 mg of a yellow solid which constituted a 39% yield.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]3[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=3)[CH2:28][CH2:27]2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:39][CH:37]([C:34]1[N:33]=[C:32]([N:29]2[CH2:28][CH2:27][CH:26]([CH2:25][O:24][C:21]3[CH:20]=[CH:19][C:18]([C:11]4[CH:12]=[CH:13][C:8]([C:6]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:7])=[CH:9][CH:10]=4)=[CH:23][CH:22]=3)[CH2:31][CH2:30]2)[O:36][N:35]=1)[CH3:38]
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(C(=O)N5CCCC5)cc4)cc3)CC2)n1
Yield: 4.2 %

Procedure:
The title compound (4 mg, 4%) was prepared as a yellow solid from [4-(1-pyrrolidinylcarbonyl)phenyl]boronic acid (44 mg, 0.2 mmol), 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (prepared as in Example 24, Step 1, 76 mg, 0.2 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 1, Step 1, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.58 (s, 4H), 7.53 (d, 2H, J=8.8 Hz), 6.96 (d, 2H, J=8.8 Hz), 4.26-4.16 (m, 2H), 3.88 (d, 2H, J=6.4 Hz), 3.70 (t, 2H, J=7.0 Hz), 3.52 (t, 2H, J=6.6 Hz), 3.18-3.08 (m, 2H), 2.99-2.84 (m, 1H), 2.15-1.85 (m, 7H), 1.57-1.40 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 475 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]([O:8][CH:9]([C:11](OCC)=[O:12])[CH3:10])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])([N+:16]([O-:18])=[O:17])[CH:5]=[CH:4][C:3]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:46]([O-:48])=[O:47])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:45])([F:44])[F:43])[CH:32]([O:49][CH:50]([C:52](OCC)=[O:53])[CH3:51])[C:31]=1[Cl:57].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2]1[CH:7]([O:8][CH:9]([CH2:11][OH:12])[CH3:10])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:26])([F:28])[F:27])([N+:16]([O-:18])=[O:17])[CH:5]=[CH:4][C:3]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:46]([O-:48])=[O:47])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:44])([F:43])[F:45])[CH:32]([O:49][CH:50]([CH2:52][OH:53])[CH3:51])[C:31]=1[Cl:57]
Reactant: CCOC(=O)C(C)OC1C(Cl)=C(OC2=C(Cl)C(OC(C)C(=O)OCC)C(c3ccccc3C(F)(F)F)([N+](=O)[O-])C=C2)C=CC1(c1ccccc1C(F)(F)F)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(CO)OC1C(Cl)=C(OC2=C(Cl)C(OC(C)CO)C(c3ccccc3C(F)(F)F)([N+](=O)[O-])C=C2)C=CC1(c1ccccc1C(F)(F)F)[N+](=O)[O-]

Procedure:
A solution of 2-chloro-α,α,α-trifluoro-p-tolyl-3-(1-carbethoxyethoxy)-4-nitrophenyl ether (17.32 g, 0.04 mole) in dry ether (500 ml) is treated at -10° C. with a suspension of lithium aluminum hydride (1.9 g) in ether (approximately) 100 ml) added with stirring over ten seconds. The temperature increases to about 0° to 10° C. and after a total of 45 seconds, the reaction mixture is quenched by pouring, with stirring, onto ice/dilute sulfuric acid. The ether phase is washed with water, dried, filtered through activated silica gel, and the solvent removed to give 2-chloro-α,α,α-trifluoro-p-tolyl-3-(1-hydroxymethylethoxy)-4-nitrophenyl ether as a dark oil, yield 14 g.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]([CH2:28][CH3:29])[C:7](=[O:27])[CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1)C.[OH-].[Na+]>O1CCCC1>[CH2:28]([N:6]([C:7](=[O:27])[CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1)[CH2:5][C:4]([OH:30])=[O:3])[CH3:29]
Reactant: CCOC(=O)CN(CC)C(=O)CCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC(=O)O)C(=O)CCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of 46.7 g (112 mmole) of N-ethyl-N-[1-oxo-4-[1-[(phenylmethoxy)carbonyl]-4-piperidinyl]butyl]glycine ethyl ester in tetrahydrofuran at ambient temperature is added 200 mL of 1N aqueous sodium hydroxide, and the heterogeneous mixture is stirred vigorously for 1 hour. The reaction mixture is concentrated in vacuo and the residual aqueous mixture is diluted with water and extracted with methyl tert-butyl ether (3×). The aqueous layer is acidified to pH 3 with potassium bisulfate, causing an oil to form. The mixture is extracted with methyl tert-butyl ether (3×). The combined organic layers are washed with brine (2×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil is subjected to high vacuum to give N-ethyl-N-[1-oxo-4-[1-[(phenylmethoxy)carbonyl]-4-piperidinyl]butyl]glycine (35.5 g). MS (FAB) 391 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)OC2CCN(CCCOC3C=CC=CC=3N)CC2)C=CC=CC=1.C(S(Cl)(=O)=O)C.CS(Cl)(=O)=O>>[C:1]1([CH:7]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH2:29][CH3:36])(=[O:28])=[O:27])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CS(=O)(=O)Nc1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: CCS(=O)(=O)Cl
Agent: CS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (c) was repeated except for using 4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine obtained in Example 1 (b) and ethanesulfonyl chloride instead of 4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine and methanesulfonyl chloride to give the desired compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:18][CH2:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:18][CH2:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCO[C@@H]1CN(c2cccc(C(=O)OC)c2)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCO[C@@H]1CN(c2cccc(C(=O)OC)c2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-ethoxypiperidin-1-yl)benzoate obtained in Example (177a) (24 mg, 0.09 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (15.1 mg, 0.09 mmol), WSC hydrochloride (49.7 mg, 0.26 mmol) and HOBt (11.7 mg, 0.09 mmol), to obtain 17.1 mg of the title compound as a yellow oily substance (46%).
Reaction SMILES: [CH2:1]1[O:4][C@H:2]1[CH3:3].[SH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1>>[OH:4][C@@H:2]([CH3:3])[CH2:1][S:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: C[C@H]1CO1
Product: COC(=O)c1ccc(SC[C@H](C)O)cc1

Procedure:
150 mg of (S)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (S)-methyl 4-(2-hydroxypropylthio)benzoate. 650 mg of (S)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 350 mg of (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (S)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.3 (M)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.C1(C)C=CC=CC=1>CS(C)=O>[CH3:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7](=[O:18])[C:8]3=[CH:9][C:10]=2[F:17])[CH2:28]1
Reactant: CC1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 55 °C
Yield: 76 %

Procedure:
Forty grams of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and 28.4 g (2.1 eq) of 2-methyl piperazine were put in suspension in DMSO (800 mL) under nitrogen blanket. The mixture was heated to 55° C. during 24 hours. Subsequently, toluene (200 mL) was added, the reaction mixture was cooled to 5° C., and held at this temperature overnight. The solution was filtered and dried under vacuum to obtain 43.5 g after assay (76% yield) of gatifloxacin.
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[NH:19]1C(C2C(=O)N3C=CC=CC3=NC=2)=N[N:21]=[N:20]1>>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]2[N:12]([CH:13]=1)[C:4](=[O:5])[C:3]([C:1]1[NH:2][N:21]=[N:20][N:19]=1)=[CH:9][N:10]=2)[CH3:18]
Reactant: CCOC(=O)C(C#N)=CNc1ccc(CC)cn1
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Product: CCc1ccc2ncc(-c3nnn[nH]3)c(=O)n2c1
Yield: 28 %

Procedure:
The title compound (28% yield, m.p. 289°-290.5° with decomposition) was prepared from ethyl 2-cyano-3-(5-ethyl-2-pyridylamino)acrylate in a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in Example 2.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:14]2[CH3:30])=[CH:9][CH:8]=1.[Li+].[OH-].CO.O>C1COCC1>[CH3:30][C:14]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])=[CH:12][CH:11]=2)[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:15]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)CCOc1ccc(-n2c(-c3ccccc3)cc(-c3ccccc3)c2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)cc(-c2ccccc2)n1-c1ccc(OCCC(=O)O)cc1
Temperature: 40 °C
Yield: 18.9 %

Procedure:
A mixture of 3-[4-(2-methyl-3,5-diphenyl-pyrrol-1-yl)-phenoxy]-propionic acid methyl ester (51 mg; 0.12 mmol) and LiOH (5.4 mg; 0.23 mmol) in THF (1.0 mL)/MeOH (0.5 mL)/H2O (0.4 mL) was heated at 40° C. for 4 h then quenched with aq. citric acid. Product was extracted into EtOAc then washed with water and satd NaCl; then dried over MgSO4, filtered through silica with an EtOAc wash, concd then purified by MPLC (silica; 0-->100% EtOAc in hexanes gradient) yielding product as a grey solid (9 mg). 1H NMR (CDCl3) δ 7.53-7.48 (m, 2H), 7.41 (m, 2H), 7.24 (m, 1H), 7.20-7.08 (m, 7H), 6.91 (m, 2H), 6.55 (s, 1H), 4.27 (t, J=6.4 Hz, 2H), 2.89 (t, J=6.2 Hz, 2H), 2.23 (s, 3H).
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][C:37]#[N:38].O>CS(C)=O>[O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:35][CH2:36][C:37]#[N:38])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cl)c(Nc2cc(Nc3ccc(OCC4CO4)cc3)ncn2)c1
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCN(c1cc(Nc2ccc(OCC3CO3)cc2)ncn1)c1cc(Cl)ccc1Cl
Reaction time: 20 h
Yield: 26 %

Procedure:
To a solution of 4-{4-[2,3-epoxypropoxy]anilino}-6-(2,5-dichloroanilino)pyrimidine (Reference Example 9, 1.4 g) in DMSO (3.75 ml) was added K2CO3 (1.1 g) and 3-bromopropionitrile (0.66 ml) and the reaction stirred for 20 hours. The mixture was poured into water and extracted with EtOAc. The organic extract was dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with DCM:MeOH; 99:1 to give the product (436 mg, 26%) as a colourless oil. NMR: 2.66 (1H, t), 2.78-2.92 (3H, m), 3.76 (1H, dd), 3.82-4.36 (3H, m), 5.28 (1H, s), 6.82 (2H, d), 7.38 (2H, d), 7.57 (1H, dd), 7.72 (1H, m), 8.25 (1H, s), 8.89 (1H, s); m/z 456(MH+).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH3:17][NH2:18]>CCO>[CH3:17][NH:18][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1
Reactant: CN
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Temperature: 145 °C
Yield: 74.7 %

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.4 g, 1.30 mmol), methanamine (33% in EtOH, 2.0 ml, 16.1 mmol) and EtOH (3.0 ml) was heated in a micro wave oven at 145° C. for 30 min. The volatiles were evaporated in vacuum and the crude product was chromathographed twice on a silica column using EtOAc/MeOH (4:1) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the title compound (0.25 g, 74%). The amine was converted into hydrochloric acid salt and crystallized from EtOH/MeOH/DEE. M.p. 225° C. MS m/z (rel. intensity, 70 eV) 257 (M+, 1), 123 (76), 78 (35), 77 (bp), 51 (97).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[OH:21][C:22]1[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:26][CH:27]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[O:18]1[CH2:19][CH2:20][N:15]([C:4]2[C:5]3[O:10][C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[C:6]=3[N:7]=[C:2]([C:26]3[CH:27]=[C:22]([OH:21])[CH:23]=[CH:24][CH:25]=3)[N:3]=2)[CH2:16][CH2:17]1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Oc1cccc(-c2nc(N3CCOCC3)c3oc4ccccc4c3n2)c1
Temperature: 90 °C
Yield: 83.9 %

Procedure:
Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2-d]pyrimidine (ASA66) (48.7 mg, 168 □mol, 1.0 eq) and 3-Hydroxyphenylboronic acid pinacol ester (MW 220) (148 mg, 672 □mol, 4.0 eq) in 1,2 dimethoxyethan and 2 M Na2CO3 (3:1) (4 mL) for 5 min. Dichloro 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (MW 732) (3.07 mg, 4.20 □mol, 0.025 eq) was added and the reaction mixture was heated to reflux (90° C.) for 15.5 h. The red solution was cooled and diluted with EtOAc (6.5 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc. 32% in water)=5:4:1 (6.5 mL), then NH4Cl (sat.) and brine (2×), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography gave a colorless solid (49 mg, 85%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(O)CO>[Cu]I.C(O)CCC>[CH2:9]([NH:16][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: OCCO
Product: O=C(O)c1ccccc1NCc1ccccc1
Temperature: 100 °C
Yield: 48 %

Procedure:
Copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μL, 1.20 mmol), 2-chlorobenzoic acid (157 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 1-butanol (1.0 mL) were used and heated to 100° C. for 72 hours. The above workup procedure was followed and gave 2-(N-benzyl)aminobenzoic acid (109 mg, 48% isolated yield) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:35])[C@@H:18]([NH:27]C(=O)OC(C)(C)C)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)[C:3]1=[O:36].Cl.[Cl:39][Si](C)(C)C.CO>C(OCC)C>[ClH:39].[NH2:27][C@@H:18]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:37])([CH3:1])[C:3]2=[O:36])[CH2:16][CH2:15]1)=[O:35]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N1CCC(N2C(=O)C(C)(C)c3ccccc32)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC1(C)C(=O)N(C2CCN(C(=O)[C@@H](N)CCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A mixture of (S)-tert-butyl 1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-ylcarbamate (2.79 g, 5.52 mmol, EXAMPLE 1, Step 3) and 1 mol/L hydrochloride in diethyl ether (25 mL) was stirred at room temperature. After 4 h, a mixture of chlorotrimethylsilane (2 mL) and methanol (4 mL) was added to the reaction suspension. The whole mixture changed to a clear solution and was stirred for 3 h. The mixture was concentrated in vacuo and the residue was diluted with diethyl ether and re-concentrated to remove methanol completely. The obtained solid was washed with diethyl ether to give the title compound (2.05 g, 84%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O>>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1
Reactant: OB(O)c1ccco1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: c1coc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2-furylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 296.0 (M+H)+, retention time 1.72 minutes.