Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+]>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a mixture of ethyl 1-((4-fluorophenyl)carbamoyl)cyclopropane-carboxylate (8.9 g, 35.4 mmol) in EtOH/THF (50/50 mL, Guangdong Guanghua Chem. Co. Ltd.) was added KOH (3.98 g, 70.8 mmol, Guangdong Guanghua Chem. Co. Ltd.) aqueous solution dropwise via a syringe. The reaction was stirred at RT overnight under N2. The mixture was concentrated in vacuo. The residue was then acidified to pH 2 with 5 N HCl and extracted with EtOAc (150 mL×4), the combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized in EtOAc/n-hexane (1:40 v/v) to give the title compound as a white solid (7.66 g, 97%).
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:5]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:6]3[CH:5]=[C:4]([C:3]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])[CH:9]=[CH:8][CH:7]=3)[CH:11]=2)[NH:16][N:17]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCCC4)c3)cc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (30 mg, 83 μmol) was dissolved in pyrrolidine (0.35 ml, 4.15 mmol) and the mixture was stirred at 90° C. for 16 h. The mixture was then concentrated and the crude product purified by flash silica gel chromatography using a gradient of 10% v/v of methanol in ethyl acetate to afford {3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-pyrrolidin-1-yl-methanone as a yellow solid (22 mg, 55 μmol, 67% yield). 1H-NMR (500 MHz, d6-MeOH) δ 8.82 (d, 1H), 8.39 (d, 1H), 7.83 (t, 1H), 7.79 (td, 1H), 7.66 (dd, 1H), 7.55-7.59 (m, 2H), 7.48 (ddd, 1H), 7.20 (d, 1H), 7.11 (dt, 1H), 3.88 (s, 3H), 3.63 (t, 2H), 3.52 (t, 2H), 2.02 (m, 2H), 1.92 (m, 2H). MS: m/z 399 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[C:7](=[O:20])[C:6]2=[O:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7](=[O:20])[C:6]2=[O:21]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 2-(5-methoxy-2,3-dioxoindolin-1-yl)acetate (0.65 g, 2.231 mmol) in DCM (20 ml), TFA (2.58 ml, 33.5 mmol) was added. The reaction was stirred at room temperature for 72 hours, then the solvent was evaporated to dryness affording 2-(5-methoxy-2,3-dioxoindolin-1-yl)acetic acid that was used in the next step without further purification (0.48 g, 2.041 mmol, 91% yield). MS/ESI+ 235.9 [MH]+
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]3[C:24]=2[CH:25]=[N:26][C:27]([CH3:34])=[N:28]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F)c1cccc(F)c1OC

Procedure:
In the same way as in Example 29,123 mg (0.40 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 72 mg (0.60 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.22 ml of titanium tetraethoxide are reacted to give (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol. 170 mg of crude imine are cyclized in the same way as in Example 29 at −30° C. with 2.8 ml (2.8 mmol) of 1 M boron tribromide solution to give the desired product. Purification by chromatography on silica gel (dichloromethane/ethyl acetate 0-40%) gives 21 mg of product.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:17].COC(C)(C)C>C(OCC)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[CH2:12][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2ccccc2)cc1CO
Reactant: BrP(Br)Br
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Cc1ccc(-c2ccccc2)cc1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 180.1 %

Procedure:
To a solution of 1.33 g (6.71 mmol) of 5-phenyl-2-methylbenzylalcohol in 30 ml of dry diethyl ether was added dropwise 0.91 g (3.02 mmol) of phosphorous tribromide with ice-cooling. After the mixture was stirred for 3 hours with ice-cooling, to the reaction solution were added ice water and tert-butyl methyl ether with ice-cooling. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium hydrogencarbonate and water, then dried and concentrated to obtain 1.42 g (5.44 mmol) of 5-phenyl-2-methylbenzylbromide as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.CC(C)([O-])C.[K+].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl>CN(C)C=O>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][O:9][CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:5]1
Reactant: Fc1ccccc1CCl
Reactant: CN(C)C1(c2ccccc2)CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(OCc2ccccc2F)CC1
Temperature: 0 °C
Yield: 14.1 %

Procedure:
2.75 g of 4-dimethylamino-4-phenylcyclohexanol were dissolved in 20 ml of dimethylformamide; 1.55 g of potassium tert.-butoxide were added and stirring was carried out for 45 minutes, before 2.0 g of 2-fluorobenzyl chloride were added dropwise in the course of 30 minutes. After stirring overnight, the mixture was added to 25 ml of ice-water and extracted repeatedly with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting crude product (3.41 g) was separated on silica gel with methanol/ethyl acetate (V:V=1:1). 580 mg of [4-(2-fluoro-benzyloxy)-1-phenylcyclohexyl]dimethylamine were obtained in the form of a white solid which, as described for Example 1, was converted into 370 mg of the corresponding hydrochloride using chlorotrimethylsilane and water in 2-butanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@@H:13]1[O:23][CH2:24][CH3:25].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@@H:13]2[O:23][CH2:24][CH3:25])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)O)cc1Cl
Reactant: CCOC(=O)N1CC[C@@H](N)[C@@H](OCC)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2cc(Cl)c(C)[nH]2)[C@@H](OCC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 4-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 27, 0.87 g, 5.55 mol) and ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.2 g, 5.55 mmol) in dichloromethane (150 mL) was added HOBT (850 mg, 0.55 mmol) and N-methyl morpholine (1.82 mL, 1.66 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (1.9 g, 9.99 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with the addition of 2N HCl (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica, 35% ethyl acetate in pet ether) afforded Ethyl (3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate 1.6 g (80%) as brown solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[C:27]1([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CS(C)=O>[C:27]1([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:12]2([CH3:11])[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Solvent: O
Product: CC1(NCCCCc2ccccc2)COc2ccc3c(c2O1)CC(=O)N3
Temperature: 85 °C
Yield: 26.3 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.05 g, 2.80 mmole) and phenylbutylamine (1.99 ml, 12.5 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, 200 ml of water was added and the mixture was extracted twice with 300 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 1% methanol/CH2Cl2 as eluant. The free base of the title compound (0.26 g, 30%) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.25 g of the (S) enantiomer of the title compound as an tan solid fumarate, one-half hydrate, m.p. 185°-186° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][N:6]=1)=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([Cl:16])=[O:13])=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Product: COC(=O)c1ccc(C(=O)Cl)cn1

Procedure:
Starting material (10(c)) was prepared as follows. Pyridine 2,5-dicarboxylic acid 2-methyl ester (10(a)) (9.0 g; 0.05 mole) was added to stirring thionyl chloride (25 mL) and the mixture refluxed gently for 2.5 hours. The excess thionyl chloride was removed in vacuo and the residual solid azeotroped with toluene (2×25 mL) to give 5-chlorocarbonyl-pyridine-2-carboxylic acid methyl ester (10(b)) which was used crude in the next reaction.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO.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:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:22][CH:23]=1)(=[O:30])[CH3:29]
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Reactant: CC(=O)Nc1ccc(Br)cc1
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: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1ccc(-c2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 39.3 %

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.200 g, 0.77 mmol), 1-bromo-4-acetamidobenzene (0.158 g, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mmol), and 2M aqueous sodium carbonate solution (2 mL) in 15 mL of tetrahydrofuran:methanol (1:1) to give the title compound (0.101 g, 40%) as an amorphous solid. FDMS m/e=348 (M+). EA calculated for C22H25N3O.¼ H2O: C, 75.07; H, 7.16; N, 11.94. Found: C, 74.94; H, 7.00; N, 11.61.
Reaction SMILES: C(O/[CH:4]=[C:5](\[CH3:12])/[C:6](=O)[C:7]([F:10])([F:9])[F:8])C.O.[NH2:14][NH2:15]>CCO>[CH3:12][C:5]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:14][NH:15][CH:4]=1
Reactant: CCO/C=C(\C)C(=O)C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1c[nH]nc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Into a 100-mL round-bottom flask, was placed (E)-4-ethoxy-1,1,1-trifluoro-3-methylbut-3-en-2-one (compound 261.1, 2.6 g, 14.3 mmol) in EtOH (20 mL). Hydrazine hydrate (1.8 mL, 38 mmol) was added and the resulting solution was stirred for 2 h at 80° C. The reaction was concentrated under reduced pressure to obtain the title compound as a yellow oil (2 g, crude).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[C:20]([CH3:40])[CH:19]=1>>[CH3:39][C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[N:29]1[CH2:30][CH2:31][N:26]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[CH:19][C:20]=2[CH3:40])=[O:25])[CH2:27][CH2:28]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 72.4 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (482 mg) described in Preparation Example 1 and (4-bromo-2-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (774 mg) described in Preparation Example 130 and by the reaction and treatment in the same manner as in Example 32, the title compound (662 mg) was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:26]=[CH:27][CH:28]=1)[O:18][C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:26]=[CH:27][CH:28]=1)[O:18][C:19]1[S:23][C:22]([CH2:24][NH2:25])=[CH:21][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(Oc2cccc(OCc3ccccc3)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Oc2cccc(OCc3ccccc3)c2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Next, to a solution of lithium aluminum hydride (27 mg, 0.716 mmol) in tetrahydrofuran (2.0 mL) was added a solution of 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile obtained above (110 mg, 0.358 mmol) in tetrahydrofuran (1 mL), and the solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (80 mg, 72%) as a red solid. This compound was used in the next reaction without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([CH2:36]I)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-hydroxy-4-biphenyl carbonitrile and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (157 mg, 66%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[NH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([NH2:38])=[O:37])=[CH:39][CH:40]=2)=[O:25])[CH2:7]1
Reactant: NCc1ccc(C(N)=O)cc1
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CNC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 103.4 %

Procedure:
Example 54 was prepared in an analogous manner to Example 43 from Intermediate 13 (0.079 g) and 4-aminomethylbenzamide (0.032 g) using N,N-dimethylformamide as solvent to yield the title compound (0.0837 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12][CH2:11][CH2:10][O:9]1.[Cl-].[CH3:14][O:15][C:16](=[O:20])[C:17](O)=[O:18]>[Zn]>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:18])[C:16]([O:15][CH3:14])=[O:20]
Reactant: COC(=O)C(=O)O
Reactant: Brc1ccccc1C1OCCO1
Agent: [Cl-]
Agent: [Zn]
Product: COC(=O)C(=O)c1ccccc1C1OCCO1

Procedure:
174.5 g of 1-bromo-2-(1,3-dioxolan-2-yl)-benzene was reacted via the zinc-organic compound with 102 g of oxalic acid monomethyl ester chloride, analogously to Example 2. Yield: 41.6 g.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH:21](OCC)=[O:22]>C(Cl)Cl>[C:2]([O:6][C:7](=[O:11])[C@@H:8]([NH:9][CH:21]=[O:22])[CH3:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC=O)C(=O)OC(C)(C)C

Procedure:
To a suspension of (2S) alanine tert-butyl ester hydrochloride (3.63 g, 20 mmol) in a mixture of ethyl formate (10 mL) and DCM (5 mL) was added diisopropylethylamine (3.83 mL, 22 mmol) and the reaction mixture was refluxed overnight. The solvents were evaporated and the residue was then triturated in Et2O and filtrated. The filtrates were evaporated and the residue was filtered through a short pad of silica using ethyl acetate as eluent. Evaporation of the solvent afforded the sub-title compound as a colorless oil which crystallised upon standing (2.806 g, 81%): 1H NMR (400 MHz CDCl3) δ 1.43 (3H, d), 1.50 (9H, s), 4.55 (1H, m), 6.31 (1H, br s), 8.16 (1H, s).
Reaction SMILES: C([Li])(CC)C.[N:6]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.CN(C)CCN(C)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(OCC)C.O>[N:6]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc21
Reactant: CCOC(=O)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 37.6 %

Procedure:
A 1.3 M solution of sec-butyl lithium in cyclohexanes (1642 mL, 2.13 mol) was added dropwise to a solution of 1,1-dimethylethyl 2,3-dihydro-1H-indole-1-carboxylate (300 g, 1.37 mol) and N,N,N′,N′ tetramethyl-1,2-ethanediamine (248 mL, 1.64 mol) in dry diethyl ether (2.5 L) at −78° C. The reaction mixture was stirred for 2 hours at this temperature and ethyl chloroformate (143.9 mL, 1.50 mol) was added dropwise to the mixture at −78° C. After the addition, the reaction was allowed to warm to room temperature overnight. Water (1 L) was added carefully to the mixture and the organic layer was separated and dried (Na2SO4). The solution was concentrated and the residue was purified by silica-gel column chromatography (PE:EA=10:1), giving 150 g (38%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][NH:13][C@@H:14]1[CH2:31][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([O:29]C)=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:13]([CH3:12])[C@@H:14]2[CH2:31][N:18]3[C:19]4[C:24]([C:25]([CH2:26][C:27]([OH:29])=[O:28])=[C:17]3[CH2:16][CH2:15]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:11])=[CH:6][CH:7]=1
Reactant: CN[C@H]1CCc2c(CC(=O)OC)c3ccccc3n2C1
Reactant: O=C(O)Cc1ccc(F)cc1
Product: CN(C(=O)Cc1ccc(F)cc1)[C@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (4-fluorophenyl)acetic acid and methyl [(7S)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 395.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:14]5[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Yield: 61 %

Procedure:
tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (120 mg, 0.316 mmol) and 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (76 mg, 0.35 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (100 mg, 62%) as a white solid: ESI MS m/z 519 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[N:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24].Cl>O1CCOCC1.CC(O)=O>[Br:27][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:2]2[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([C:11]3[S:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[N:3]=2)=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]
Reactant: Nc1ccc(Br)c(C(=O)O)c1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Br)c(C(=O)O)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A 18-mL vial was charged with 4-chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine (87 mg, 0.318 mmol, 1.05 eq.), 5-amino-2-bromo-benzoic acid (65 mg, 0.3 mmol, 1 eq.). AcOH (1 ml) and 4 N HCl in dioxane (5 drops). The resulting mixture was stirred under Ar at 110° C. for 2 hr. After cooling to rt, The volatile material was removed under reduced pressure and the residue was treated with dichloromethane to give the title compound (105 mg, 77% yield).