Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([O:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO.[BH4-].[Na+]>O>[C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:18][CH:19]=1)=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)OCc2ccc(C=O)cc2)cc1C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)OCc2ccc(CO)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.6 g (5 mmol) of the aldehyde obtained in Example 45, 50 ml of THF and 50 ml of methanol are introduced into a round-bottomed flask. 100 mg (2.5 mmol) of sodium borohydride are added in small portions and the mixture is stirred at room temperature for 4 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated.
Reaction SMILES: [OH-].[Ba+2].[OH-].[C:4]1([CH3:13])[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:23]1[N:24]=[C:25]([N:29]([C:33]2[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:34]=2[O:40][CH3:41])[CH2:30][CH2:31][CH3:32])[S:26][C:27]=1[CH3:28]>C(O)C.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:23]1[N:24]=[C:25]([N:29]([C:33]2[CH:38]=[C:37]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH3:13])[CH:36]=[CH:35][C:34]=2[O:40][CH3:41])[CH2:30][CH2:31][CH3:32])[S:26][C:27]=1[CH3:28]
Reactant: Cc1ccccc1B(O)O
Reactant: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(Br)ccc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ba+2]
Solvent: O
Solvent: CCO
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(-c2ccccc2C)ccc1OC

Procedure:
1.96 g of barium hydroxide, 0.52 g of o-tolyl-boronic acid and 40 mg of palladium diacetate are added in succession to 1 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-bromo-2-methoxyphenyl)-N-propylamino]thiazole, in solution in 25 ml of ethanol and 0.8 ml of water. The reaction mixture is heated for 1 hour under reflux; after returning to room temperature, it is filtered on Celite. After evaporation of the solvent, the residue is taken up in dichloromethane. The organic phase is washed with water and then dried over sodium sulphate. The evaporation residue is purified on silica gel; eluent dichloromethane/cyclohexane 9/1 (v/v). The expected product is obtained in the form of a powder; m.p.=55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:21]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:21][C:4]1[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Yield: 100 %

Procedure:
The product from Example 128a (1.0 g, 2.97 mmol) was reduced with SnCl2 following the procedure from Example 1f giving the title compound as a clear oil (911 mg, 100%).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH2:20])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][CH:8]=[O:10])=[CH:14][CH:13]=1
Reactant: COc1nc(Br)ccc1N
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1nc(Br)ccc1NC=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
A mixture of acetic anhydride (8.54 mL, 24.63 mmol) and formic acid (12.8 mL, 24.63 mmol) was stirred at room temperature for 40 min. To this mixture 6-bromo-2-methoxypyridin-3-amine (5.000 g, 24.63 mmol) in 30 mL of THF was added dropwise. The resulting solution was heated at 60° C. with stirring for 16 h. Upon cooling, the reaction mixture was poured into icewater. The resulting precipitate was filtered to give N-(6-bromo-2-methoxypyridin-3-yl)formamide (5.690 g, 24.63 mmol, 100% yield) as light brown solid. LC-MS (M+Na)+=231.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:34])[CH2:10][C@@:11]1([C:28]2[S:29][C:30](Br)=[CH:31][CH:32]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1.[C:35](=[O:38])([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>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:34])[CH2:10][C@@:11]1([C:28]2[S:29][C:30]([C:21]3[CH:26]=[CH:25][C:24]([C:35]4[O:38][CH:15]=[N:14][CH:13]=4)=[CH:23][CH:22]=3)=[CH:31][CH:32]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1
Reactant: O=C(C[C@]1(c2ccc(Br)s2)CCN(C(=O)c2ccccc2)CCS1(=O)=O)NOC1CCCCO1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: O=C(C[C@]1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCN(C(=O)c2ccccc2)CCS1(=O)=O)NOC1CCCCO1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(5-oxazolyl)phenylboronic acid pinacol cyclic ester obtained in Preparation 9-2) were added N-(2-tetrahydropyranyloxy)-2-[(S)-4-benzoyl-7-(5-bromo-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (1.70 g), tetrakis(triphenylphosphine)palladium(0) (103 mg) and 2M aqueous sodium carbonate solution (5 ml) and the mixture was stirred at 80° C. for 4 hours. After evaporation of solvent, ethyl acetate and water were added and the insolubles were filtered off. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (100:1 to 200:3) to give N-(2-tetrahydropyranyloxy)-2-[(S)-4-benzoyl-7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide as a pale yellow amorphous powder (1.28 g).
Reaction SMILES: [CH2:1](C1(N2C=CC=N2)C=C(C)C=CC1)CC#C.C(C1(N2C=CC=N2)C=CC=C(C)C1)CC#C.C[C:34]1[N:38]([CH2:39][CH2:40][C:41]#[C:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[N:37]=[CH:36][C:35]=1[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH3:1][C:36]1[C:35]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[CH:34][N:38]([CH2:39][CH2:40][C:41]#[C:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[N:37]=1
Reactant: C#CCCC1(n2cccn2)C=C(C)C=CC1
Reactant: Cc1c(-c2ccccc2)cnn1CCC#Cc1ccccn1
Agent: C#CCCC1(n2cccn2)C=CC=C(C)C1
Product: Cc1nn(CCC#Cc2ccccn2)cc1-c1ccccc1
Yield: 10 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 1, from 255 mg (1.21 mmol) of 1-but-3-ynyl-5-methylphenyl-1H-pyrazole and 1-but-3-ynyl-3-methylphenyl-1H-pyrazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 33 mg (0.11 mmol, 10%) of 2-(4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine and 2-(4-(5-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a orange oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:37]1[C:42]([CH:43]=[O:44])=[CH:41][C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=1>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O.C(OCC)(=O)C>[CH:43]([C:42]1[CH:41]=[C:40]([O:45][CH3:46])[C:39]([O:47][CH3:48])=[CH:38][C:37]=1/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])=[O:44]
Reactant: C=CC(=O)OC
Reactant: COc1cc(Br)c(C=O)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)/C=C/c1cc(OC)c(OC)cc1C=O
Temperature: 25 °C

Procedure:
6.2 ml of methyl acrylate, 25 ml of triethylamine, 270 mg of Pd(OAc)2 and 1.5 g of tri-(o-tolyl)-phosphine were added to a solution of 14.7 g of 6-bromoveratraldehyde in 100 ml of dimethylacetamide. The reaction mixture was heated for 4 hours to 110° C., then left to cool to room temperature and poured into a mixture of ethyl acetate and water. The crude product was extracted and purified by chromatography on silica gel and yielded 10.8 g of methyl (E)-3-(2-formyl-4,5-dimethoxy-phenyl)-acrylate as a yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][C:29]1[S:33][CH:32]=[C:31]([CH2:34][N:35]2[CH2:55][CH2:54][C:38]3([O:43][CH2:42][CH2:41][N:40]([C:44]([C:46]4[N:47]=[C:48]([CH:51]([CH3:53])[CH3:52])[S:49][CH:50]=4)=[O:45])[CH2:39]3)[CH2:37][CH2:36]2)[CH:30]=1)(C(C)(C)C)(C)C>O1CCCC1>[OH:26][CH2:27][CH2:28][C:29]1[S:33][CH:32]=[C:31]([CH2:34][N:35]2[CH2:55][CH2:54][C:38]3([O:43][CH2:42][CH2:41][N:40]([C:44]([C:46]4[N:47]=[C:48]([CH:51]([CH3:52])[CH3:53])[S:49][CH:50]=4)=[O:45])[CH2:39]3)[CH2:37][CH2:36]2)[CH:30]=1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4csc(CCO[Si](C)(C)C(C)(C)C)c4)CC3)C2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4csc(CCO)c4)CC3)C2)cs1
Reaction time: 2 h

Procedure:
Tetrabutylammonium fluoride (1M in tetrahydrofuran, 2.1 mL) was added to a solution of (9-((5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 278, step d) (0.80 g) in tetrahydrofuran (10 mL). After 2 h, the solution was evaporated in vacuo and the residue partitioned between saturated sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organic solutions were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography, eluting with 20:1 ethyl acetate:triethylamine. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a gum. Yield 0.61 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][CH3:27])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Temperature: 110 °C
Yield: 54 %

Procedure:
To a stirred mixture of 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (0.730 g, 1.95 mmol), 2-methoxyphenylboronic acid (0.300 g, 1.97 mmol) in saturated sodium carbonate solution (10 ml) and 1,4-dioxane (10 ml) was added palladium(II) acetate (0.088 g, 0.39 mmol) followed by triphenylphosphine (0.103 g, 0.39 mmol) at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to reflux at 110° C. for one hour and monitored by TLC. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, elution with 50% ethyl acetate/n-hexanes) to afford 4-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XI) (0.47 g, 53%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:24]=[C:25]=[O:26]>>[F:23][C:3]([F:2])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][N:16]([C:25]([NH:24][CH:4]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:5]2)=[O:26])[CH2:15]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccccc1
Reactant: [N-]=C=O
Agent: Cl
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccccc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)benzhydryloxy]azetidine hydrochloride (133) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[N:5]=1)C.Br.[OH-].[Na+]>>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[N:5]=1
Reactant: CCOc1cccc(C(C)=O)n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1cccc(O)n1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
48.5 g of 2-ethoxy-6-acetylpyridine were introduced into 145 ml of hydrogen bromide solution (30 percent strength solution in glacial acetic acid) and the mixture was heated to 95° C. A further 176 ml of hydrogen bromide solution (30% strength solution in glacial acetic acid) were added dropwise at this temperature. The mixture was stirred for 3 hours at 95° C. and then cooled to room temperature. It was poured into ice-water and neutralized to pH 7 using 50 percent strength aqueous sodium hydroxide solution. The mixture was subsequently extracted 3 times with methyl tert-butyl ether. The aqueous phase was concentrated. The residue which remained was stirred 4 times with acetone. After the combined acetone phases had been concentrated, there remained 38.5 g of 2-hydroxy-6-acetylpyridine as a colorless solid (m.p.: 115-117 C).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH3:21][N:22](C=O)C>CCOC(C)=O.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.[C-]#N.[Zn+2].[C-]#N>[C:21]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)#[N:22]
Reactant: CN(C)C=O
Reactant: O=C1CCC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2CCC(=O)N2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 5-(4-trifluoromethanesulfonyloxyphenyl)-2-pyrrolidinone (2.45 g, 8.22 mmol), tetrakis(triphenylphosphine)palladium (475 mg, 0.41 mmol), and zinc cyanide (1.45 g, 12.3 mmol) in 10 mL of DMF was flushed with nitrogen three times and then stirred at 80° C. After 3 hr, the mixture was cooled down to rt, diluted with EtOAc (10 mL), and filtered through a cake of Celite. The solid was washed with EtOAc, and the filtrates were combined and concentrated. Chromatography on a Biotage 40+M cartridge using 9:1 v/v EtOAc/CH3OH as the eluant gave 2.68 g (100%) of the title compound containing trace amount of DMF: 1H NMR (CD3OD) δ 1.90-1.97 (m, 1H), 2.43-2.51 (m, 2H), 2.60-2.67 (m, 1H), 4.85 (t, J=7.2, 1H), 7.41 (d, J=8.8, 2H), 7.65 (d, J=8.5, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:17])[C:4]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:5]=2.B(F)(F)F.CCOCC.[CH:27](O)([CH3:29])[CH3:28]>>[CH:27]([O:1][C:2]1[C:3](=[O:17])[C:4]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:5]=2)([CH3:29])[CH3:28]
Reactant: CC(C)O
Reactant: O=C1C=C(O)C(=O)c2cc3ccccc3cc21
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)OC1=CC(=O)c2cc3ccccc3cc2C1=O
Temperature: 70 °C

Procedure:
4 grams of 2-hydroxy-1,4-anthraquinone synthesized as described above, 20 ml of isopropanol and 12 ml of borontrifluoride etherate were heated at 70° C. overnight, yielding the desired product, 2-isopropoxy-1,4-anthraquinone. After cooling, the solution was filtered, dried, and washed with standard KHSO4. Finally, the product was washed with water and dried at room temperature overnight.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[F:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: NCc1ccccc1F
Reactant: Clc1nc2c(Br)cccn2n1
Product: Fc1ccccc1CNc1cccn2nc(Cl)nc12

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-fluoro-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 8.60 mmol), and 2-fluorobenzylamine (1.11 mL, 9.72 mmol) in a manner analogous to Example 2d. Product isolated as an off-white solid, (1.45 g. 61%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.11 (d, J=6.9 Hz, 1H), 7.39-7.26 (m, 2H), 7.23-7.10 (m, 3H), 6.98 (t, J=14.0, 7.3 Hz, 1H), 6.43 (d, J=8.0 Hz, 1H), 4.53 (d, J=6.1 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1.[Br:21][Si](C)(C)C>C(#N)CC>[Br:21][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1
Reactant: N#Cc1cccc(F)c1-n1cc2c(Cl)ncc(F)c2n1
Reactant: C[Si](C)(C)Br
Solvent: CCC#N
Product: N#Cc1cccc(F)c1-n1cc2c(Br)ncc(F)c2n1
Temperature: 80 °C
Yield: 100 %

Procedure:
2-(4-Chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-fluorobenzonitrile (520 mg, 1.79 mmol) was suspended in propionitrile (35 mL), under an atmosphere of nitrogen and bromotrimethylsilane (0.646 mL, 6.76 mmol) was added. The reaction mixture was heated at 80° C. for 4.5 hours. The resultant mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (600 mg, 100% yield). This was used in the next step without purification. LCMS (Method F): RT=3.30 min, m/z: 335 [M+H+].
Reaction SMILES: Br[C:2]1C=C2C(=C[CH:11]=1)NC(=O)CC2C(NC[C@@H](C(O)=O)NC(=O)C1C=CC(C(NCC2C=CC=C(O)C=2)=O)=CC=1Cl)=O.[Cl:42][C:43]1[CH:68]=[C:67]([C:69]([NH:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([OH:79])[CH:74]=2)=[O:70])[CH:66]=[CH:65][C:44]=1[C:45]([NH:47][C@H:48]([C:62]([OH:64])=[O:63])[CH2:49][NH:50][C:51]([C:53]1O[C:55]2[CH:61]=[CH:60][CH:59]=[CH:58][C:56]=2[CH:57]=1)=[O:52])=[O:46]>>[Cl:42][C:43]1[CH:68]=[C:67]([C:69]([NH:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([OH:79])[CH:74]=2)=[O:70])[CH:66]=[CH:65][C:44]=1[C:45]([NH:47][C@H:48]([C:62]([OH:64])=[O:63])[CH2:49][NH:50][C:51]([CH:53]1[CH2:11][CH2:2][C:55]2[C:56](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:57]1)=[O:52])=[O:46]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc3ccccc3o2)C(=O)O)c(Cl)c1
Reactant: O=C1CC(C(=O)NC[C@H](NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)c2cc(Br)ccc2N1
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)C2CCc3ccccc3C2)C(=O)O)c(Cl)c1

Procedure:
N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(DL-7-methoxy-1,2,3,4,4αβ,9,10,10αβ-octahydro-2β-phenanthrenecarbonyl)]amino-L-alanine; 3-(6-bromo-2-oxo-1,2,3,4-tetrahydroquinoline-4-carbonyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(benzofuran-2-carbonyl)amino-L-alanine;
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:7]=[N:6][C:5]=1[Cl:14].[Li+].[OH-]>C1COCC1>[CH2:10]([C:8]1[CH:7]=[N:6][C:5]([Cl:14])=[C:4]([CH:9]=1)[C:3]([OH:15])=[O:2])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cnc(Cl)c(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1cnc(Cl)c(C(=O)O)c1

Procedure:
In analogy to the procedure described in example 124.1, 5-butyl-2-chloro-nicotinic acid methyl ester was treated with LiOH in THF to give 5-butyl-2-chloro-nicotinic acid as colorless crystals. MS: m/e=212.2 [M−H−].
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@:9]21[CH2:14][N:13]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:12][CH2:11][CH2:10]2)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:13]2[CH2:12][CH2:11][CH2:10][C@@:9]3([CH2:23][CH2:24][CH2:25][CH2:26][C@H:8]3[NH2:7])[CH2:14]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@]12CCCN(Cc1ccc(F)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCCC[C@@]12CCCN(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 1085.4 %

Procedure:
A solution of [(6S,7R)-2-(4-fluorobenzyl)-2-aza-spiro[5.5]undec-7-yl]-carbamic acid tert-butyl ester (6.3 g, 1.4 mmol) in dichloromethane (30 mL) was treated with trifluoroacetic acid (30 mL) and stirred at room temperature for 1 hour. The solvent was removed under vacuum to give a residue. The residue was treated with 1.0 N aqueous sodium hydroxide. The mixture was extracted with dichloromethane and the organic phase was washed with water and saturated aqueous sodium chloride. The solvent was removed under vacuum to give an oil (4.2 g). 1H NMR (300 MHz, CDCl3) δ7.30-7.24 (m, 2H), 7.01-6.94 (m, 2H), 3.37 (m, 2H), 2.62 (m, 1H), 2.44 (m, 1H), 2.24 (m, 2H), 2.09 (m, 1H), 1.81 (m, 1H), 1.65-1.24 (m, 13H). Mass spec (ES+) m+/z 277.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[CH:18]=2)[N:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+].[CH:34](I)([CH3:36])[CH3:35].[OH-].[Na+]>CC(N(C)C)=O.O.CO>[CH:34]([N:25]1[CH2:26][CH2:27][C@H:23]([O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][N:11]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=2[CH3:1])[C:6]([OH:8])=[O:7])[C:20]3=[O:21])[CH2:24]1)([CH3:36])[CH3:35]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(O[C@H]3CCNC3)cc2c1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(O[C@H]3CCN(C(C)C)C3)cc2c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
4-methyl-3-[4-oxo-6-[(3S)-pyrrolidin-3-yloxy]quinazolin-3(4H)-yl]benzoic acid (0.21 g) isopropyliodide (0.073 ml), and potassium carbonate (0.318 g) were stirred in dimethylacetamide (2 ml) for 18 hours at room temperature. Additional isopropyliodide (0.073 ml) was added and stirring continued for a further 24 hours. To the reaction mixture was added MeOH (2 ml), water (0.5 ml) and 2N NaOH (0.58 ml) and the reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give a brown oil which solidified on standing for 18 hours in vacuo to give 3-[6-{[(3S)-1-isopropylpyrrolidin-3-yl]oxy}-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (297 mg); NMR Spectrum: (DMSOd6) 0.99 (m, 6H), 1.80 (m, 1H), 2.13 (s, 3H), 2.33 (m, 2H), 2.78 (m, 4H), 5.03 (m, 1H), 7.46 (m, 3H), 7.70 (d, 1H), 7.87 (s, 1H), 7.96 (d, 1H), 8.16 (s, 1H); Mass Spectrum: M+H+ 408.