Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=12)=[O:2].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:13]([N:4]1[CH:5]=[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]2=[C:3]1[CH:1]=[O:2])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=Cc1[nH]cc2c1OCCO2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc2c(c1C=O)OCCO2
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of aldehyde 19 (0.8 g, 5.2 mmol) in dichloromethane was added (BOC)2O (1.1 g, 5.2 mmol), triethylamine (1.1 g, 10.4 mmol), and 4-dimethylaminopyridine (DMAP) (61 mg, 0.5 mmol). The reaction mixture was stirred for 3 h and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexane/ethyl acetate (3:1) as eluent to yield a colorless crystalline product (1.2 g, 90%): mp 94-95° C.; 1H NMR (300 MHz, CDCl3) δ10.24 (s, 1H), 6.88 (s, 1H), 4.38 (m, 2H), 4.22 (m, 2H), 1.60 (s, 9H); 13C NMR (75 MHz, CDCl3) δ180.9, 148.8, 143.2, 134.2, 116.6, 107.9, 85.1, 66.1, 64.9, 27.9; FT-IR (CDCl3) 2930, 2859, 1653, 1544, 1460, 1380, 1322 cm−1; Anal. Calcd for C12H15NO5: C, 56.91; H 5.97; N, 5.53. Found: C, 56.90; H, 5.80; N, 5.73.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15].CCN(CC)CC>C1COCC1>[CH2:13]([NH:16][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:12])[CH:14]=[CH2:15]
Reactant: CC(C(=O)O)c1ccc(O)cc1
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCNC(=O)C(C)c1ccc(O)cc1
Reaction time: 3 h

Procedure:
N,N′-Carbonyldiimidazole (22.65 g, 140 mmol) was added to commercially available 2-(4-hydroxyphenyl)propionic acid (21 g, 127 mmol) in THF (100 mL). Gentle warming and gas evolution was observed. The resulting mixture was stirred for 3 h. Allylamine (10.9 g, 190.5 mmol) and Et3N (19.2 mL, 190.5 mmol) were added dropwise, and the mixture was stirred overnight. The reaction was quenched with water (200 mL) and the organic phase was extracted with ethyl acetate (50 mL×3). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (elution with ethyl acetate). Phenol 49.1 was obtained as a white solid. MS ESI m/e: 206 (M−H).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:36])[N:13]2[CH2:25][C:24]3[C:23](=[O:26])[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[NH:16][C:15]=3[CH:14]2[C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[O:36]=[C:12]([N:13]1[CH2:25][C:24]2[C:23](=[O:26])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:16][C:15]=2[CH:14]1[C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)/[CH:11]=[CH:10]/[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(/C=C/C(=O)N2Cc3c([nH]c4ccccc4c3=O)C2c2ccc3c(c2)OCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(/C=C/C(=O)N2Cc3c([nH]c4ccccc4c3=O)C2c2ccc3c(c2)OCO3)cc1

Procedure:
(E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoic acid methyl ester (149 mg, 0.30 mmol), (prepared as in Example 30) was suspended in a 1:1 mixture of 1 N aqueous sodium hydroxide:methanol (10 mL) and heated to reflux for 8 h. The reaction mixture was treated with aqueous HCl to pH 1, resulting in a white precipitate. The precipitate was collected by filtration and washed with water (30 mL) and diethyl ether (160 mL) to yield the product as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:3]([OH:7])[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[OH-].[Na+].[C:21]([O-])(O)=O.[Na+].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[CH3:21][O:5][C:4](=[O:6])[C@H:3]([OH:7])[C@@H:2]([NH:1][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@@H](c1ccccc1)C(O)C(=O)O
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a suspension of 15.0 g (55.5 mmol, thus only 67%) (2RS,3S)-2-Amino-3-hydroxy-2-phenylpropionic acid (from Example 3) in 250 ml methanol one carefully adds dropwise at room temperature 5 ml of concentrated H2SO4 and heated for 6 hours under reflux. 50 ml H2 0 are added and the pH adjusted to 6.8 with 50% NaOH at +5° C. Subsequently the methanol is removed by vacuum distillation, the mixture cooled to +5° C. and reacted with 10 g (120 mmol) NaHCO3 and 8.4 ml (72 mmol) benzoylchloride are added dropwise over 20 minutes. After further stirring for 2 hours the precipitated raw product is vacuum filtered, recrystallized out of 150 ml of methanol and dried to a colorless product at 50° C. in a vacuum drying vessel.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>>[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:45][CH2:46]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](C2CCCC2)N2C[C@H](CN3CCC(CCCc4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 82.1 %

Procedure:
The title compound was prepared from 22 mg (0.053 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclopentyl)acetic acid, 4-(methoxy)benzyl ester (from EXAMPLE 15, Step E) and 13 mg (0.054 mmol) of 4-(3-phenylpropyl)piperidine.HCl using a procedure analogous to that described in EXAMPLE 1, Step J to provide 26.5 mg (81%) of the title compound: RF: 0.25 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.18-1.95 (m, 18H), 2.21-2.89 (m, 11H), 3.14-3.29 (m, 4H), 3.80 (s, 3H), 5.09 (ABq, J=11.9, 2H), 6.87 (d, J=8.7, 2H), 7.14-7.35 (m, 12H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH3:12])[C:9]1([CH2:20][CH:21]=C(C)C)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH3:12])[C:9]1([CH2:20][CH:21]=[O:25])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: CC(C)=CCC1(C(=O)OC(C)(C)C)C(C)CN1C(=O)OC(C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1CN(C(=O)OC(C)(C)C)C1(CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of an optically-active compound of 3-methyl-2-(3-methyl-but-2-enyl)-azetidine-1,2-dicarboxylic acid di-tert-butyl ester (44.5 g) in chloroform/methanol (310 ml/310 ml) cooled to −70° C. was flowed ozone air for 1 hour. To the reaction mixture was added a solution of triphenylphosphine (44.7 g) in chloroform (45 ml) in small batches, and the mixture was warmed to room temperature. To the mixture were added saturated aqueous sodium thiosulfate solution (200 ml) and water (300 ml), and the mixture was extracted with chloroform (500 ml). The separated organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound (95.0 g), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([OH:13])[C:4]=1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])[CH3:2]>CO.C1COCC1.[Pd]>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([OH:13])[C:4]=1[C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCc1c(C(=O)OCc2ccccc2)c(O)nc2ccccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(C(=O)O)c(O)nc2ccccc12
Temperature: 40 °C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
Benzyl 4-ethyl-2-hydroxyquinoline-3-carboxylate (1.2 g) was suspended in methanol (12 mL) and THF (6 mL), followed by addition of 5% Pd—C (120 mg), and the mixture was stirred at 40° C. for 1 day. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure to obtain 4-ethyl-2-hydroxyquinoline-3-carboxylic acid (0.85 g). This compound was used in the subsequent step without purification.
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([CH3:30])[CH:22]=1)[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1.[C:31]1([CH3:44])[CH:36]=[CH:35][C:34]([S:37]([O:40]CC=C)(=[O:39])=[O:38])=[CH:33][CH:32]=1.[C:45]1(C)C=CC=C[CH:46]=1>>[C:31]1([CH3:44])[CH:32]=[CH:33][C:34]([S:37]([O-:40])(=[O:38])=[O:39])=[CH:35][CH:36]=1.[CH2:1]([N+:2]([CH3:31])([CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)[CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([CH3:30])[CH:22]=1)[CH:45]=[CH2:46]
Reactant: Cc1ccccc1
Reactant: C=CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc(NCCCN(C)CCCNc2ccc([N+](=O)[O-])c(C)c2)ccc1[N+](=O)[O-]
Product: C=CC[N+](C)(CCCNc1ccc([N+](=O)[O-])c(C)c1)CCCNc1ccc([N+](=O)[O-])c(C)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
N1-Methyl-N3-(3-methyl-4-nitrophenyl)-N1-{3-[(3-methyl-4-nitrophenyl)amino]propyl}-1,3-propanediamine (60.2 g, 0.14 mol) from step 7.1 was heated under reflux with allyl p-toluene sulfonate (34.0 g, 0.16 mol) in 500 ml toluene for 6 hours. As the reaction progressed the product separated out in the form of an oily substance. This oil was separated from the supernatant liquid by decanting and dried. On further cooling the oil initially solidified to a glassy material and after drying could be crushed to afford the product as a brown powder. Yield: 66.0 g (72.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:15]([O:17][CH2:18][CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[N:29]1[CH2:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][C:38]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:42][CH2:41][NH:40][CH2:39]2)[CH2:31][CH2:30]1)[CH3:16]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:4]=1[C:5]([N:40]1[CH2:41][CH2:42][C:38]([CH2:37][CH2:36][N:32]2[CH2:33][CH2:34][CH2:35][N:29]([C:21]3[N:20]([CH2:19][CH2:18][O:17][CH2:15][CH3:16])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=3)[CH2:30][CH2:31]2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:39]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(C#N)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C#N)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-cyanobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][NH:6][CH3:7].O.Cl[CH2:10][C:11]([CH3:13])=[CH2:12]>C(Cl)(Cl)Cl>[OH:3][CH2:4][CH2:5][N:6]([CH3:7])[CH2:10][C:11]([CH3:13])=[CH2:12]
Reactant: CNCCO
Reactant: C=C(C)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)CN(C)CCO

Procedure:
20.0 g of sodium hydroxide was added to 56.33 g (0.75 mol) of 2-hydroxy-N-methylethylamine and 101.61 g water, after which 45.28 g (0.50 mol) of 1-chloro-2-methyl-2-propene was slowly added dropwise at room temperature. Upon completion of the dropping, the system was allowed to react for 15 hours at 80° C. Upon completion of the reaction, the 150 g of chloroform added and the system was washed with a sodium carbonate aqueous solution to remove the unreacted 2-hydroxy-N-methylethylamine, 2-hydroxy-N-methylethylamine hydrochloride, and sodium hydroxide, which yielded a chloroform solution of N-hydroxyethyl-N,2-dimethyl-2-propene-1-amine. 150 g of a 4 N hydrochloric acid aqueous solution was added to the chloroform solution, the N-hydroxyethyl-N,2-dimethyl-2-propene-1-amine was converted into a hydrochloride and extracted into the aqueous phase, and the water was removed by freeze drying, which yielded 55.50 g (0.34 mol; 67% yield) of 2-propene-1-aminium, N-hydroxyethyl-N,2-dimethyl, hydrochloride in the form of a white powder. The structure of the 2-propene-1-aminium, N-hydroxyethyl-N,2-dimethyl, hydrochloride thus obtained was confirmed by 1H-NMR (400 MHz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:18]1[CH:19]=[C:20]([CH3:26])[C:21]([Cl:25])=[C:22]([CH3:24])[CH:23]=1>>[Cl:25][C:21]1[C:22]([CH3:24])=[CH:23][C:18]([C:6]2[CH:7]=[C:2]([CH3:1])[N:3]=[N:4][CH:5]=2)=[CH:19][C:20]=1[CH3:26]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnn1
Reactant: Cc1cc(Br)cc(C)c1Cl
Product: Cc1cc(-c2cc(C)c(Cl)c(C)c2)cnn1

Procedure:
The title compound is prepared from 3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridazine and 5-bromo-2-chloro-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=0.91 min; Mass spectrum (ESI+): m/z=233/235 (Cl) [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1.[OH-].[Na+]>COCCO>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:29]=[C:27]([NH:26][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[N:28]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: N=C(N)Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(F)cc3)n2)s1
Yield: 89.6 %

Procedure:
To a mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21 g) and N-(4-fluoro-phenyl)-guanidine nitrate (2.0 mmol, 0.44 g) in 2-methoxyethanol (5 mL) was added NaOH (40 mg). The reaction mixture was refluxed under N2 for 24 h. The solvent was evaporated to dryness and the residue was purified by flash chromatography (EtOAc/PE, 2:1) and recrystallisation from EtOAc/PE to afford the title compound as brown crystals (269 mg, 89%). 1H-NMR (300 MHz, CDCl3) δ 2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 6.93 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.03 (m, 2H, Ph-H), 7.58 (m, 2H, Ph-H), 8.40 (d, 1H, J=5.3 Hz, pyrimidinyl-H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][CH:6]=1.C1C(=O)N([Br:19])C(=O)C1>CC#N.CCOC(C)=O>[Br:19][C:6]1[S:5][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(C)cs1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(C)c(Br)s1
Temperature: 50 °C
Yield: 50.5 %

Procedure:
The reaction solution of ethyl 4-methylthiazole-2-carboxylate of preparation 83 (240 mg, 1.40 mmol), NBS (277 mg, 1.14 mmol) in CH3CN (5 mL) was heated at 50° C. for overnight under nitrogen. ˜20% starting material was present by LCMS. Additional portion of NBS (70 mg) was added. The reaction solution was heated at 60° C. for 4 hr, diluted with EtOAc (30 ml), washed with water (2×20 mL), brine, dried over sodium sulfate and purified with a silica gel column by ISCO CombiFlash® chromatography eluting with 0%-20% EtOAc/Heptane to give the title compound as a yellowish oil (177 mg, 50.5%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f12) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:15][CH:14]([NH2:16])[CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C)C=O.O>[N+:30]([C:29]1[C:24]([NH:16][CH:14]2[CH2:13][N:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]=3)[CH2:15]2)=[N:25][CH:26]=[CH:27][CH:28]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NC1CN(c2ccc3ccccc3n2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1NC1CN(c2ccc3ccccc3n2)C1
Yield: 83.3 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-amine hydrochloride (0.90 g, 3.84 mmol) in dry dimethylformamide (15 mL) was added sodium carbonate (1.22 g, 11.5 mmol) and 2-chloro-3-nitro-pyridine (608 mg, 3.84 mmol). The reaction mixture was stirred and heated at reflux for 14 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (20% to 50% ethyl acetate in petroleum ether) to give 3-nitro-N-(1-(quinolin-2-yl)azetidin-3-yl)pyridin-2-amine (1.05 g, 3.20 mmol, 85% yield) as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[C:20]([N+:37]([O-])=O)=[C:21]([CH:34]=[CH:35][CH:36]=2)[O:22][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[H][H]>O1CCCC1.[Ni]>[NH2:37][C:20]1[C:19]([NH:18][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:36][CH:35]=[CH:34][C:21]=1[O:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1N

Procedure:
To a solution of Example 44B (2.76 g) in tetrahydrofuran (125 ml) in a stainless steel bottle was added nickel catalyst (2.76 g). The mixture was stirred for 1 hour under 30 psi of hydrogen at ambient temperature. The mixture was filtered through a nylon membrane to remove the catalyst and the title compound was obtained upon evaporation of the solvent (2.54 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([NH2:10])[CH2:6][C@@H:5]1C)(=[O:3])[CH3:2].[CH2:12](N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([NH:10][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=2)[C@@H:6]([CH3:12])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=O)N1CCN(N)C[C@@H]1C
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(NC(=O)c2ccc(F)cc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (S)-1-acetyl-4-amino-2-methylpiperazine (320 mg) and triethylamine (0.57 ml) in dichloromethane (10 ml) was added 4-fluorobenzoyl chloride (0.27 ml) at 0° C. The mixture was stirred at ambient temperature for 3 hours, washed with water and brine. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with a mixture of methanol and chloroform (1:9) to give (S)-N-(4-acetyl-2-methyl-1-piperazinyl)-4-fluorobenzamide (50 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[CH:28]=[C:27]([O:30][CH3:31])[CH:26]=[CH:25][C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(O)c(B(O)O)c1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cccc(OC)c4O)n3)n2)c1
Yield: 16 %

Procedure:
6-(2-Hydroxy-3-methoxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-5-methoxyphenylboronic acid in 16% yield using method F; δH [2H6]-DMSO 13.72,(1H, b), 12.48,(1H, b), 8.39,(1H, d), 8.32,(1H, d), 8,27-8.14,(4H, m), 7.72,(1H, d), 7.67,(1H, s), 7.09,(1H, d), 7.04-6.90,(3H, m), 3.86,(6H, s); MS 401 (MH)+; HPLC retention time (system 1) 3.98 minutes.
Reaction SMILES: [CH3:1]S(Cl)(=O)=O.C(Cl)Cl.O[CH2:10][CH2:11]/[C:12](=[CH:22]\[S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[C:13](=[S:21])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O>[C:24]1([S:23]/[CH:22]=[C:12]2/[C:13](=[N:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)/[S:21][CH2:10][CH2:11]/2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:15]1([N:14]2[CH2:10][CH2:11][C:12](=[C:22]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:1])[C:13]2=[S:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC/C(=C\Sc1ccccc1)C(=S)Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C(\Sc1ccccc1)=C1\CCS\C1=N/c1ccccc1
Product: CC(Sc1ccccc1)=C1CCN(c2ccccc2)C1=S
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.13 g of methanesulfonyl chloride was added to 10 ml of methylene chloride suspension including 0.4 g of (E)-4-hydroxy-N-phenyl-2-(phenylthiomethylene)butanethioamide and 0.11 g of triethylamine. The resulting solution was stirred at room temperature for 2 hours, and added with water, extracted with ethyl acetate. The organic layer was washed with brine, and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.05 g of (Z)—N-((E)-3-(phenylthiomethylene)dihydrothiophen-2(3H)-ylidene) aniline and 0.05 g of 1-phenyl-3-(1-(phenylthio)ethylidene)pyrrolidine-2-thione.