Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[C:22](Cl)(=[O:26])C(Cl)=O.[OH-:28].[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:13][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[CH3:1])[CH:12]=[CH:11][C:10]=1[C:22]([OH:26])=[O:28]
Reactant: O=C(Cl)C(=O)Cl
Reactant: [OH-]
Reactant: Cc1cccc(NC(=O)c2ccccc2C)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2ccccc2C)ccc1C(=O)O
Temperature: 3 °C
Reaction time: 5 h
Yield: 65.8 %

Procedure:
To a solution of 3-(2-methylbenzoylamino)toluene (50.0 g, 0.222 mole) in methylene chloride (50 mL) which is cooled to 3° C. is added aluminum chloride (88.8 g, 0.666 mole) under nitrogen atmosphere over a period of about 10 minutes. The mixture is cooled to 3° C., and thereto is added dropwise oxalyl chloride (25.2 mL, 0.289 mole) at 3-7° C. The mixture is stirred at 2-7° C. for 5 hours. After confirming the disappearance of the starting materials, the reaction mixture is diluted with methylene chloride (100 mL), and thereto is added ice water to quench the reaction. After distilling off methylene chloride, the resulting aqueous suspension is refluxed for 30 minutes and then cooled to room temperature. The resulting crystals are separated by filtration and the wet crystals are dried at 60° C. to give the crude product (58.33 g). To the crude product (29.17 g) are added 2.5 mol/L aqueous sodium hydroxide solution (400 mL) and toluene (100 mL), and insoluble materials are removed by filtration and then separated into two layers. The aqueous layer is washed twice with toluene (100 mL) and neutralized with 6 mol/L hydrochloric acid (300 mL). The precipitated crystals are separated by filtration and dried at 60° C. and then recrystallized from methanol (540 mL) to give the desired product (19.67 g, yield 65.8%, purity by HPLC 99.4%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[CH2:8]([O:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[CH2:8]([O:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCCCCBr
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#CCCCCn1cc(C(=O)OCc2ccccc2)c2ccccc21
Temperature: 0 °C

Procedure:
1.1 equivalents of 5-bromovaleronitrile are added to 40 mmol of 3-indolecarboxylic acid benzyl ester dissolved in tetrahydrofuran. After cooling to 0° C., 1.8 g of sodium hydride are added portionwise. After one hour of reaction at 0° C. and 14 hours at room temperature, ethyl acetate and water are added. The organic phase is separated and washed several times in succession with an aqueous phase containing hydrochloric acid followed by a basic aqueous phase. After drying and evaporation, the residue is purified by chromatography on silica gel using an ethyl acetate/pentane (2:3) mixture as solvent, and the expected product is obtained.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[CH:31]=[C:30]([C:32](=[O:34])[CH3:33])[C:29](=[O:35])[N:28]([CH:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO.C(Cl)Cl>[ClH:1].[C:32]([C:30]1[C:29](=[O:35])[N:28]([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:26]2[N:27]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([N:12]4[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]4)=[CH:16][N:17]=3)[N:23]=[CH:24][C:25]=2[CH:31]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Reaction time: 8 h
Yield: 76 %

Procedure:
Anhydrous HCl gas was bubbled through a solution of 4-[6-(6-acetyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester (398 mg, 0.74 mmol, prepared as in Example 32), in MeOH/CH2Cl2 (10 mL/10 mL) at room temperature for ˜5 min. The reaction mixture was stirred overnight and then solvent was removed under reduced pressure. The remaining solid was triturated with hot ethyl acetate and dried to provide 6-acetyl-8-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride (329 mg, 76%). mp >300° C. Anal. Calc'd for C23H27N7O2.4.25 HCl: C, 46.94; H, 5.35; N, 16.66. Found: C, 46.77; H, 5.33; N, 16.30. M++1: Calc'd: 434.2, Found 434.2.
Reaction SMILES: COC1C=CC(S([N:12]2[CH2:17][CH:16]=[CH:15][C@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:13]2[C:24]([OH:26])=O)(=O)=O)=CC=1.Cl.C([NH:35]O)C1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(OCC)(=O)C>[C:18]1([CH:14]2[CH:15]=[CH:16][CH2:17][NH:12][CH:13]2[C:24]([NH2:35])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ONCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N2CC=C[C@H](c3ccccc3)[C@@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)C1NCC=CC1c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (+)-(2R*-3R*)-1-(4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxylic acid (65 mg, 0.17 mmol) (from Example 20), is added benzylhydroxylamine hydrochloride (32 mg, 0.20 mmol), dicyclohexylcarbodiimide (41 mg, 0.20 mmol) and dimethylaminopyridine (27 mg, 0.22 mmol). The resulting mixture is stirred overnight, diluted with ethyl acetate and filtered through Celite™ and evaporated. The crude product is purified by chromatography elution with 1:1 hexane-ethyl acetate to provide (+)-(2R*-3R*)-N-benzyloxy-1-4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:31]3[CH2:36][CH2:35][S:34][CH2:33][CH2:32]3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: C1CSCCN1
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCSCC3)C2)cc1
Temperature: 150 °C

Procedure:
5.00 g (12.1 mmol) of the compound from Example 45A, 3.57 g (36.4 mmol) of thiomorpholine and 5.03 g (36.4 mmol) of potassium carbonate were added to 76 ml of DMF and heated in 5 portions in a single-mode microwave (Emrys Optimizer) at 150° C. for 1.5 h. For workup, the reaction solutions were combined and filtered, and the residue was purified by means of preparative HPLC. Yield: 3.07 g (67% of theory)
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=CC=1S(Cl)(=O)=O.[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C(OC(=O)[C@H](C(C)C)N)(C)(C)C.C([O:53][C:54](=[O:61])[C@H:55]([CH2:57][CH:58]([CH3:60])[CH3:59])[NH2:56])(C)(C)C>>[CH3:59][CH:58]([CH3:60])[CH2:57][C@H:55]([NH:56][S:33]([C:20]1[CH:21]=[CH:22][C:23]2[O:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:31][C:32]=2[CH:19]=1)(=[O:35])=[O:34])[C:54]([OH:61])=[O:53]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-leucine-t-butyl ester, (S)-4-methyl-2-(phenoxathiine-2-sulfonylamino)-pentanoic acid is obtained; mp 120-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7](SC#N)[N:6]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:5]3[C:4]=2[CH:3]=1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].O>CN1CCN(C)C1=O.C(O)C>[C:23]([NH:27][C:7]1[N:6]2[N:15]=[C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:5]2[C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[N:8]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: N#CSc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12
Reactant: CC(C)(C)N
Solvent: CN1CCN(C)C1=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)Nc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12
Reaction time: 3 h

Procedure:
A solution of 9-chloro-5-thiocyanato-2-(2-furyl)[1,2,4]triazolo-[1,5-c]quinazoline (2 g) in 1,3-dimethylimidazolidone (28 ml) is added to tert-butylamine (2 ml). The mixture is stirred for 3 hours under nitrogen, and then is diluted with ethanol (20 ml), and treated with water (20 ml). The resulting precipitate is collected, recrystallized from 2-methoxyethanol, and dried in high vacuum to afford pure 5-tert-butylamino-9-chloro-2-(2-furyl)-[1,2,4]triazolo-[1,5-c]quinazoline, mp above 330° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][O:22][CH3:23])=[CH:19][C:14]=2[O:13][CH2:12][C:11]1([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][O:33][CH3:34])=[CH:27][CH:26]=1)[CH3:24].ClCCl.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1.O>N1C=CC=CC=1>[CH3:23][O:22][CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:44]([C:41]3[CH:42]=[CH:43][C:38]([CH3:48])=[CH:39][CH:40]=3)(=[O:46])=[O:45])[C:11]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][O:33][CH3:34])=[CH:29][CH:30]=3)([CH3:24])[CH2:12][O:13][C:14]=2[CH:19]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 103.2 %

Procedure:
(3RS,4RS)-4-(8-Hydroxyoctyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (80 mg, 0.17 mmol) was dissolved in pyridine (2 ml) and dichloromethane (0.5 ml) and then cooled to 0° C. p-Toluenesulfonylchloride (0.12 g, 0.63 mmol) was added thereto and the mixture was stirred for 6 hours at room temperature. Water was added thereto at 0° C. and the reaction solution was extracted with ethyl acetate, washed with saturated saline and then dried over magnesium sulfate. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 110 mg (yield: ~100%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:40][CH3:41])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35](O)=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1.C(OC1C=C(OC2CC3C(C(=O)N(C)CCCCC=CC4C(C([NH:77][S:78]([CH:81]5[CH2:83][CH2:82]5)(=[O:80])=[O:79])=O)(NC3=O)C4)C2)C2C(=C(C)C(OC)=CC=2)N=1)C>>[Br:1][C:2]1[C:3]([O:40][CH3:41])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([NH:77][S:78]([CH:81]4[CH2:83][CH2:82]4)(=[O:80])=[O:79])=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(Br)c2n1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(Br)c2n1

Procedure:
The title compound (7) was prepared from 17-[8-bromo-2-ethoxy-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (6) following the procedure reported for synthesis of N-[17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (3): m/z=734 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC(C1C=CC(Cl)=CC=1)=O.[Cl-].[In+3].[Cl-].[Cl-].[CH3:31][S:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[CH:39]2>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:39]2[C:38]3[C:42](=[C:34]([CH2:33][S:32][CH3:31])[CH:35]=[CH:36][CH:37]=3)[NH:41][CH:40]=2)([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(Cl)cc1
Reactant: CSCc1cccc2cc[nH]c12
Agent: CC(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3.42 g (14.10 mmol) of ethyl 3-(4-chlorophenyl)-3-hydroxybutanoate (preparation in analogy to the synthesis of Example 88A starting from 4-chloroacetophenone and ethyl acetate) and 3.12 g (14.10 mmol) of indium(III) chloride were added to 2.50 g (14.10 mmol) of the compound from Example 8A in 100 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate, and the solid was filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 95/5) and then by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 0.98 g (17% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:21][C:22]([F:35])([F:34])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])=[O:24]>CN(C)C=O>[F:21][C:22]([F:34])([F:35])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[O:32])=[O:24]
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CCCCCNC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(NC(=O)CCCCCNC(=O)C(F)(F)F)cc1
Reaction time: 24 h

Procedure:
To 0.57 g (3 mmol) of para-amino-benzenesulfonyl azide dissolved in 5 mL dimethylformamide was added 0.9 mL (6 mmol) triethylamine, then the (2,2,2-trifluro-acetylamino)-hexanoyl chloride dissolved in 10 mL dimethylformamide was added dropwise. The mixture turned brown and was stirred under argon for 24 hrs. Solvent was evaporated, and the remaining oil was dissolved in 10 mL dichloromethane and left at room temperature for 1 hr. The precipitate was filtrated and the solution was evaporated to yield 1.10 g crude oil. The obtained compound was directly used in oligonucleotide synthesis.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[N:13]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Reactant: COC(=O)CCCCCCN
Agent: Cl
Product: COC(=O)CCCCCCNCc1ccc(-c2ncccn2)cc1

Procedure:
The title compound of Step A was prepared from 7-amino-heptanoic acid methyl ester hydrochloride, of Preparation 1, and 4-pyrimidin-2-yl-benzaldehyde, of Preparation 21, using the method described in Example 1, Step A. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, 2H), 8.37 (d, 2H), 7.42 (d, 2H), 7.16 (t, 1H), 3.85 (s, 3H), 3.64 (s, 3H), 2.62 (t, 2H), 2.28 (t, 2H), 1.55 (m, 4H), 1.32 (m, 4H); MS 328 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[C:21](=O)(OC(Cl)(Cl)Cl)[O:22]C(Cl)(Cl)Cl.[NH2:33][C@@H:34]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:35]([O:37][CH3:38])=[O:36]>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[NH:33][C@@H:34]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:35]([O:37][CH3:38])=[O:36])=[CH:16][CH:15]=1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@H](NC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1)C(=O)OC
Temperature: 2.5 °C

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine (intermediate 30.7) (200 mg, 0.65 mmol, 1.00 equiv) in dichloromethane (10 mL), triethylamine (1.2 mL). This was followed by the addition of bis(trichloromethyl) carbonate (200 mg, 0.67 mmol, 1.03 equiv) slowly with stirring at 0-5° C. The resulting solution was stirred for 1 h at room temperature. To this was added triethylamine (1 mL) followed by (S)-dimethyl 2-aminosuccinate (200 mg, 1.24 mmol, 1.91 equiv) in several batches. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10-1:5). This resulted in 50 mg (15%) of (2S)-dimethyl 2-(3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)succinate as yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:20]>[Pd].C(O)(=O)C.CO.C(#N)C>[ClH:20].[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(c2ccccc2)c2ccncc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reaction time: 96 h

Procedure:
A mixture of 62.69 g (0.256 mole) of 4-(diphenylmethyl)pyridine and 6.4 g of 10% palladium on carbon (0.006 mole) in 300 ml of glacial acetic acid and under an atmosphere of hydrogen (44 psi) was shaken on a Parr apparatus at 85° for 4 days. The reaction mixture was filtered, and the solvent was removed in vacuo from the filtate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a solid. This was dissolved in a mixture of methanol-acetonitrile, and excess ethereal hydrogen chloride was added. A precipitate was collected to give 59.13 g (80.3%) of slightly impure title compound as a white, crystalline solid, mp 273°-274° C. Part of this was recrystallized from methanol-ether to give an analytically pure sample, mp 275.5°-277° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH:12]([Cl:15])([Cl:14])[Cl:13].[OH-].[K+]>CN1CCCC1=O.CO>[Cl:13][C:12]([CH:7]([OH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([Cl:15])[Cl:14]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: ClC(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=[N+]([O-])c1cccc(C(O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a solution of 3-nitrobenzaldehyde (80 g, 0.53 mol) and chloroform (95 ml, 1.17 mol) in 320 ml of N-methylpyrrolidinone cooled to -10° C. under nitrogen was added dropwise a solution of potassium hydroxide (24 g, 0.43 mol) in 80 ml of methanol over a 40 minute period. The deep purple reaction mixture was aged for 4 hours at -5° C. before quenching into 640 ml of lN HCl and 500 ml of methylene chloride cooled to 0° C. The quench mixture was stirred and cooled for an additional 0.5 hour and then brought to ambient temperature. The methylene chloride layer was separated and washed twice with 720 ml of water, 720 ml of 10% sodium bisulfite, and again with 720 ml of water. After treatment with 9.0 g of Darco G-60 charcoal for 1 hour and filtration through Super-Cel, the organic layer was washed with 450 ml of aqueous 5% sodium bicarbonate solution and then 720 ml of water, with 65 ml of saturated salt solution added. The resulting methylene chloride solution contained 140.2 g (98.4% yield) of TMBA.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][Cl:35].O>CN(C)C=O>[Cl:35][CH2:34][CH2:33][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (45 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (187 mg) and 1-bromo-2-chloroethane (0.06 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (46 mg, yield 90%).
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[NH:12]([CH2:19][C:20]1([OH:36])[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH2:37]>C(#N)C>[O:37]=[C:2]1[N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:19][C:20]2([CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:21]2)[O:36]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O
Reactant: O=C(OCc1ccccc1)N1CCCC(O)(CNc2ccccc2)C1
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCCC2(C1)CN(c1ccccc1)C(=O)O2
Temperature: 80 °C
Reaction time: 20 h

Procedure:
N,N′-Carbonyldiimidazole (1.5 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 g) were added to benzyl 3-(anilinomethyl)-3-hydroxypiperidine-1-carboxylate (2.2 g) obtained by the above-mentioned reaction in acetonitrile (35 mL), and the mixture was stirred at 80° C. for 20 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give crude benzyl 2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.5]decane-7-carboxylate (2.0 g).