Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClS(C1C=C(C=CC=1F)C(O)=O)(=O)=O.[CH2:15]([NH2:18])[CH2:16][CH3:17].[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30](NCC)(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]>>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30]([NH:18][CH2:15][CH2:16][CH3:17])(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Reactant: CCCN
Agent: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Product: CCCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F

Procedure:
2.512 g (9.2 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 2.27 mL (27.6 mmol) propylamine following the general procedure in for 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification. 1H NMR (300 MHz, DMSO-d6) δ8.19-8.22 (d, 1H, J=7.84 Hz), 8.12-8.16 (t, 1H, J=11.59 Hz), 7.85-7.88 (d, 1H, J=9.90 Hz), 2.80-2.87 (q, 2H, J=6.82), 1.33-1.45 (m, 2H), 0.77-0.82 (t, 3H, J=7.51 Hz).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:7].[C:15](Cl)(=[O:25])[C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH2:4]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15](=[O:25])[C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:14][C:11]3[CH:10]=[CH:9][C:8]([C:6]([O:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:7])=[CH:13][CH:12]=3)=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)=[O:7])[CH2:3][CH2:2][CH3:1]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CCCCOC(=O)c1ccc(O)cc1
Product: CCCCOC(=O)c1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(C(=O)OCCCC)cc3)cc2)cc1

Procedure:
Butyl p-hydroxybenzoate and terephthalic dichloride are allowed to react in a similar procedure to Example 5. The product is recrystallized from hexane-chloroform (1:1) to give di(p-butoxycarbonylphenyl)terephthalate, m.p. 128°-131° C., as white crystals.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22](O)=[O:23])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[O:25][CH3:26].[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C>ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:22]([CH:17]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:25][CH3:26])[N:9]([CH2:8][CH2:7][O:6][S:28]([CH3:27])(=[O:30])=[O:29])[C:21]=2[CH2:20][CH2:19][CH2:18]1)=[O:23])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCNCC
Reactant: COc1cccc2c1c1c(n2CCO)CCCC1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CCCc2c1c1c(OC)cccc1n2CCOS(C)(=O)=O
Temperature: 25 °C
Yield: 117.7 %

Procedure:
9-(2-Hydroxyethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamine (11) (478 mg, 1.4 mmol) in dichloromethane (30 ml) was cooled to 0° C. and methanesulfonyl chloride (477 mg, 4.2 mmol, 324 μL) and triethylamine (420 mg, 4.2 mmol, 578 μL) were added and allowed to warm to RT overnight. The reaction was washed with 5% aqueous potassium carbonate solution. The layers were separated. The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a gum (696 mg). The crude material was purified by silica gel chromatography eluting with petrol (A): ethyl acetate (B) (75-100% B, 22 CV, 120 g, 85 mL/min) to afford Methanesulphonic acid 2-(4-diethylcarbamyl-5-methoxy-1,2,3,4-tetrahydro-carbazol-9-yl)ethyl ester (precursor compound 5) as a gum that crystallised from diethyl ether to give 346 mg (59%) of a colourless solid. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 13.1, 14.5, 20.0, 21.9, 28.0, 36.3, 36.7, 40.3, 41.8, 41.9, 54.7, 68.1, 100.0, 102.0, 109.0, 116.4, 122.0 135.1, 137.3, 153.8, and 174.6.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH3:22][N:23]([CH2:25][C:26]1[CH:27]=[C:28]([C:32]2[NH:61][C:35]3=[N:36][CH:37]=[CH:38][C:39]([C:40]4[C:41]([C:49]5[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:60])[N:57]([CH3:59])[CH3:58])=[CH:51][CH:50]=5)=[N:42][N:43]([CH2:45][CH2:46][NH:47][CH3:48])[CH:44]=4)=[C:34]3[CH:33]=2)[CH:29]=[CH:30][CH:31]=1)[CH3:24].[OH-].[Na+].CC(OC(C)=O)=O>CO.O>[CH3:58][N:57]([CH3:59])[C:56]([NH:55][C:52]1[CH:51]=[CH:50][C:49]([C:41]2[C:40]([C:39]3[CH:38]=[CH:37][N:36]=[C:35]4[NH:61][C:32]([C:28]5[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:23]([CH3:22])[CH3:24])[CH:27]=5)=[CH:33][C:34]=34)=[CH:44][N:43]([CH2:45][CH2:46][N:47]([CH3:48])[C:2](=[O:1])[CH3:4])[N:42]=2)=[CH:54][CH:53]=1)=[O:60]
Reactant: O=C(O)C(F)(F)F
Reactant: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)N(C)CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
To N′-(4-{4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(methylamino)ethyl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea-3TFA (300 mg, 0.34 mMol) in MeOH (10 mL) was added with stirring at RT, aq. 1 N NaOH and Ac2O (40 uL, 0.42 mMol). After stirring for 30 min. the reaction was diluted with water, basified with aq. 1 N NaOH (0.4 mL), extracted with (9:1) CHCl3/iPrOH, dried (Na2SO4), filtered, and evaporated to dryness under vacuum. Trituration with (1:1) Et2O and petroleum ether, filtration and drying under vacuum gave the title compound (177 mg, 90%) as an off-white solid. ESMS [M+H]+: 579.7.
Reaction SMILES: Cl[CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4].Cl.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][SH:39].C(N(CC)CC)C.CN1CCCN(C)C1=O>CO>[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][S:39][CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(Cl)c1ccccc1
Reactant: CN(C)CCS
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN1CCCN(C)C1=O
Product: CN(C)CCSC(C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1
Temperature: 60 °C
Yield: 93.1 %

Procedure:
A mixture of 0.14 g of α-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]benzeneacetamide, 0.47 g of 2-dimethylaminoethanethiol hydrochloride in 2 ml of methyl alcohol, 0.30 g of triethylamine and 3 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is heated at 60 ° C. for 48 hours. The methyl alcohol is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water. The solid is dissolved in ethyl acetate and washed with saturated NaHCO3, brine and dried with Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to a residue which is stirred with ether-hexane to give 0.15 g of beige solid. MS(CI):525(M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:22])[C:9]([C:19]([OH:21])=O)=[CH:10][N:11]2[CH2:14][CH2:15][O:16]C=O)=[CH:6][CH:5]=1)[CH3:2].[NH2:23][C:24]1[NH:28][N:27]=[N:26][N:25]=1>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:22])[C:9]([C:19]([NH:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[O:21])=[CH:10][N:11]2[CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: CCOc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(CCO)c2n1

Procedure:
7-Ethoxy-1(2-formyloxyethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.5 g) and N,N'-carbonyldiimidazole (0.4 g) in dimethylformamide (10 ml) were stirred and heated to 80° for 6 hours. 5-Amino-1H-tetrazole (0.42 g) was added and the mixture stirred and heated to 80° for 30 minutes. The solid was collected and dissolved in aqueous sodium hydroxide (10 ml, 2N) and the solution was acidified to pH 1 with dilute hydrochloric acid. The solid was filtered off, washed with water and dried, m.p. above 297° (d). (45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[C:29]([N+:36]([O-])=O)[CH:28]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>[Zn].CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([NH2:33])[CH:30]=[C:29]([NH2:36])[CH:28]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCOc1ccc(C=CC(=O)OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CCCCOc1ccc(C=CC(=O)OCCCCCCOC(=O)c2cc(N)cc(N)c2)cc1OC
Temperature: 40 °C
Yield: 102.6 %

Procedure:
3.80 g (6.98 mmol) 3,5-dinitrobenzoic acid 6-[3-(3-methoxy-4-butyloxyphenyl)acryloyloxy]hexyl ester and 1.47 g (27.48 mmol) of ammonium chloride were suspended in 75 ml of a mixture consisting of methanol:water 9:1. 9.07 g (0.139 mol) of zinc powder was then added in one portions. The reaction temperature rose to 36° C. The suspension was then heated at 40° C. for 1.5 hours. The reaction suspension was partitioned between dichloromethane and water. The resulting suspension was filtered, the organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water. The organic phase was then dried over sodium sulfate, filtered and concentrated by evaporation to yielded 3.47 g (99%) 3,5-diaminobenzoic acid 6-[3-(3-methoxy-4-butyloxyphenyl)acryloyloxy]hexyl ester as yellow oil
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][NH:4][CH2:5][C:6]1[S:10][C:9]([C:11]([N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:12])=[CH:8][CH:7]=1.[C:29]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36](=[O:56])[O:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][N:46]([CH3:55])[C:47](=[O:54])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=O)[CH2:40][CH2:39]1>>[C:29]1([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36](=[O:56])[O:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][N:46]([C:47](=[O:54])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][N:4]([CH2:5][C:6]2[S:10][C:9]([C:11](=[O:12])[N:13]([CH2:14][CH2:15][CH2:16][N:17]([C:18]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:24])[CH3:25])[CH3:26])=[CH:8][CH:7]=2)[CH2:3][C:2]([CH3:28])([CH3:27])[CH3:1])[CH3:55])[CH2:40][CH2:39]1
Reactant: CN(CCCN(C)C(=O)c1ccc(CNCC(C)(C)C)s1)C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(Cc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)s1)CC(C)(C)C
Yield: 57.1 %

Procedure:
The compound (122 mg, 0.307 mol) obtained in Example 55b and the compound (171 mg, 0.368 mmol) obtained in Example 4g were used to give the title compound (181 mg; yield, 69%) as a colorless oily substance according to the method described in Example 45b.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[N:7][C:8]([S:13][CH3:14])=[N:9][C:10]=1[CH2:11][CH3:12])=[O:4].O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[C:10]([CH2:11][CH3:12])[N:9]=[C:8]([S:13][CH3:14])[N:7]=2)[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: CCc1nc(SC)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nc(SC)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
274 mg (0.768 mmol) of 4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio)-pyrimidine-5-carboxylic acid methylester was dissolved in 5 ml of THF and 5 ml of water. 33.7 mg (0.922 mmol) of lithium hydroxide monohydrate was added and stirred at 80° C. for 12 hours. 10 ml of water was added thereto and the organic layer was batched off. The obtained aqueous layer was diluted with ethyl acetate and washed with 5 ml of 3 N hydrochloric acid and then with 5 ml of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.CN([CH:19]=[O:20])C>>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:19]=[O:20])=[CH:10][NH:11]2
Reactant: CN(C)C=O
Reactant: Brc1cccc2[nH]ccc12
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cccc(Br)c12
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
POCl3 (1.02 g, 6.63 mmol) was added dropwise to ice cold DMF (3 mL) and stirred for 15 min. 4-Bromoindole (1.00 g, 5.10 mmol) in DMF (1 mL) was added slowly. The mixture was heated to 35° C. with continuous stirring for 1.20 h (yellow precipitation was formed). The reaction mixture was cold on ice and treated with ice and 20% W/w aq. NaOH to pH 14 (pink color). Heating at reflux for 15 min. afforded a yellow clear solution, which formed a white precipitation when allowed to attain rt. The precipitation was filtered off, rinsed with ice cold water and dried under reduced pressure over weekend to give the title compound (1.14 g, 65%) as an off white solid. MS (ESI+) for C9H6BrNO m/z 224 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:21]1([CH3:38])[CH:26]=[CH:25][C:24](S(OCC2CCCCC2)(=O)=O)=[CH:23][CH:22]=1>>[CH:21]1([CH2:38][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCCCC2)c1
Yield: 54.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (201 mg, yield: 54.3%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:26]=3[CH3:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Cc1cccc(C)c1CCl
Product: Cc1cccc(C)c1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 24.6 %

Procedure:
The title compound (0.018 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, step B; 0.2 mmol) using 2,6-dimethylbenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C22H24ClN3, 365.17; found, m/z 366.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.48-7.45 (m, 4H), 7.17-7.15 (br m, 1H), 7.11-7.09 (m, 2H), 5.51 (s, 2H), 3.43-3.41 (br m, 2H), 3.39-3.37 (br m, 2H), 3.31-3.29 (br m, 2H), 3.10-3.08 (br m, 2H), 2.31 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[CH:15]=2)[C:11]2[C:6](=[C:7]([O:26]C)[C:8]([O:24]C)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].B(Br)(Br)Br.ClCCl.CO>ClCCl>[C:1]([N:4]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[CH:15]=2)[C:11]2[C:6](=[C:7]([OH:26])[C:8]([OH:24])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc([C@H]2CN(C(C)=O)Cc3c2ccc(OC)c3OC)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1Cc2c(ccc(O)c2O)[C@@H](c2ccc(O)c(O)c2)C1
Yield: 96.6 %

Procedure:
(i)1.78 g of (R)-(-)-N-acetyl-7,8-dimethoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 9 ml of dichloromethane; after adding 24 ml of 1M boron tribromide-dichloromethane solution at -30 ° C., the mixture was reacted at room temperature for 90 minutes. Then 4.4 ml of methanol was added at -30° C. The reaction solution was concentrated and subjected twice to azeotropic distillation with methanol. To the residue was added 17.8 ml of 0.1N hydrochloric acid. The crystals which separated out were collected by filtration, affording 1.46 g of (R)-(-)-N-acetyl-7,8-dihydroxy-4-(3,4-dihyroxyphenyl)-1,2,3,4-tetrahydroisoquinoline.1/4 hydrate, m.p. above 230° C. (decomposition): [α]D20 =-85° (C=1, CH3OH)
Reaction SMILES: [Cl-:1].C(OC([NH:12][C:13]([CH3:26])([CH3:25])[CH2:14][CH2:15][N+:16]1([CH3:24])[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]1)=O)C1C=CC=CC=1>[Pd].O>[ClH:1].[Cl-:1].[NH2:12][C:13]([CH3:26])([CH3:25])[CH2:14][CH2:15][N+:16]1([CH3:24])[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]1
Reactant: CC(C)(CC[N+]1(C)CCC(F)(F)CC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: [Cl-]
Solvent: O
Product: CC(C)(N)CC[N+]1(C)CCC(F)(F)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-(3-(Benzyloxycarbonylamino)-3-methylbutyl)-4,4-difluoro-1-methylpiperidinium chloride (1.78 g, 4.49 mmol) was dissolved into water (100 mL) and 10% Pd/C (300 mg) was added to the flask. It was sealed and degassed with vacuum and flushed with hydrogen from a balloon (3 times). The reaction was stirred at room temperature for 17 h. The suspension was filtered through a pad of Celite® and the solid was washed with water (2×50 mL). The filtrate was concentrated to a viscous oil which became a white foam after being dried under high vacuum (1.30 g, quant). LRMS (ESI+) for C11H23F2N2+ (221.1); Found: 221 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=O)=[CH:7][C:3]=1[CH2:4]OC.[CH3:14][O:15][CH2:16][C:17](=O)[CH3:18].[CH:20]1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>[Pt]>[CH3:20][O:13][N:11]([CH:17]([CH3:18])[CH2:16][O:15][CH3:14])[C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([CH3:4])[CH:7]=1
Reactant: O=S(=O)(O)c1ccc2ccccc2c1
Reactant: COCc1cc([N+](=O)[O-])ccc1C
Reactant: COCC(C)=O
Agent: [Pt]
Product: COCC(C)N(OC)c1ccc(C)c(C)c1
Reaction time: 2 h

Procedure:
A mixture of methyl 2-methyl-5-nitrobenzyl ether (12 g, 0.066M), methoxyacetone [20 g (used as solvent)], 2-naphthalenesulfonic acid (0.3 g) and 5% Pt/C (0.7 g) is shaken on a Parr hydrogenator maintaining the temperature below 40° with external cooling. The theoretical amount of hydrogen (0.26M) is consumed and further uptake ceases after 2 hours.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[OH2:9].[N+]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O>>[OH:9][CH2:2][C:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: O
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CO)c1ccccc1
Yield: 64.9 %

Procedure:
To a solution of 755 mg of the thus-obtained acetate in nitrobenzene were added 456 mg of finely divided AlCl3, and the mixture was heated for one hour at 120°-125° C. The reaction mixture was diluted by water and extracted with ethyl acetate. The extracted solution was washed with water, sodium hydrogencarbonate solution, water, and saturated saline solution in series and dried over MgSO4. The distillation of the solvent and purification by chromatography through silica gel column gave 490 mg (yield: 64.9%) of the 2-hydroxyacetophenone.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6]CN)[CH3:2].[CH3:15][NH:16]CC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:31].[N:32]1([CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53]([OH:55])=O)[CH:49]=[N:50][C:44]=3[NH:43][C:42]2=[O:56])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[ClH:31].[CH2:1]([O:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:16]([CH3:15])[C:53](=[O:55])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[N:41]([CH2:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:46][C:45]=2[CH:47]=1)[CH3:2]
Reactant: CCCc1c(CNC)ccc2ccccc12
Reactant: CCOc1c(CCN)cccc1OC
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)C(=O)N2
Agent: Cl
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCCN2CCOCC2)C(=O)N3)cccc1OC
Yield: 62 %

Procedure:
According to the procedure of Example 1, except substituting (2-ethoxy-3-methoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(3-morpholin-4-yl-propyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.67 g, 62%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.16 (br s, 1H), 9.97 (d, J=11 Hz, 1H), 8.40-8.30 (m, 1H), 8.02-7.91 (m, 1H), 7.53-7.46 (m, 1H), 7.24-7.18 (m, 1H), 7.09-6.93 (m, 2H), 6.71-6.63 (m, 1H), 4.79-4.62 (m, 2H), 4.55-4.40 (m, 2H), 4.21-3.85 (m, 2H), 3.80-3.75 (m, 6H), 3.45-3.37 (m, 4H), 3.09-2.86 (m, 8H), 2.08-1.97 (m, 2H), 1.30-1.26 (m, 3H); MS (ESI) m/e 524 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Cl:17][C:18]1[CH:19]=[C:20]([OH:27])[CH:21]=[N:22][C:23]=1[CH:24]1[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([O:27][C:20]2[CH:21]=[N:22][C:23]([CH:24]3[CH2:26][CH2:25]3)=[C:18]([Cl:17])[CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 59, 35.7 g, 143.86 mmol) in DMSO (97.6 mL) was added 5-chloro-6-cyclopropylpyridin-3-ol (Preparation 69, 24.4 g, 143.86 mmol) and stirred at room temperature until a solution obtained. Potassium carbonate (49.7 g, 359.65 mmol) was added portion wise maintaining the internal temperature at 15-25° C. with a cold water jacket. The reaction mixture was stirred at room temperature for 12 hours, cold water charged and the resulting slurry stirred for 90 minutes. The mixture was filtered, washed with water and dried to give the title compound as a pale yellow solid (54.0 g, 94%).
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)C2C(=C(C)C(OC)=CC=2)N=1)[CH3:12]>>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:14]([O:13][CH2:11][CH3:12])[CH:23]=[C:22]2[O:24][CH:25]1[CH2:42][CH:41]2[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]3[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]2=[O:43])[CH2:37]3)[CH2:26]1
Reactant: COc1cccc(N)c1Br
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(Br)c2n1

Procedure:
The title compound (6) was prepared from 2-bromo-3-methoxyaniline following the procedure (Steps A-J) reported for synthesis of 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-carboxylic acid (2): m/z=631 (M+H)+.