Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([NH2:13])=[S:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(NC(N)=S)cc1O
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(Nc2ccc(OC)c(O)c2)n1
Yield: 63 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 1-(3-hydroxy-4-methoxyphenyl)thiourea (150 mg, 0.76 mmol) and ethyl 3-bromopyruvate (0.095 mL, 0.76 mmol) in dry DMF (3.0 mL) was heated at 60° C. for 6 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 63% yield (139 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:21]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>ClCCl.CO>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([N:30]3[CH2:31][CH2:32][CH2:33][CH:28]([CH2:27][CH2:26][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:29]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: C1CNCC(CCN2CCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: CO
Product: O=C1Nc2cccnc2N(C(=O)N2CCCC(CCN3CCCC3)C2)c2cc(Cl)ccc21
Yield: 42 %

Procedure:
Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 3-[2-(1-pyrrolidinyl)ethyl]piperidine in a yield of 42% of theory. Colourless crystals, m.p. 136°-139° C., Rf 0.25 (Merck DC ready made TLC plates, silica gel 60 F254 ; eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].Cl>ClCCl>[C:25]([Si:22]([CH3:24])([CH3:23])[O:1][CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)N1OCCCO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCON1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 2-(3-hydroxy-propoxy)-isoindole-1,3-dione (17.5 g, 79.1 mmol) and imidazole (5.92 g, 86.1 mmol) in dichloromethane (200 mL) was added tert-butyldimethylsilyl chloride (13.2 g, 86.1 mmol). After 30 min, the reaction was transferred to a separatory funnel and shaken with dilute aqueous hydrochloric acid (400 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to afford 2-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-isoindole-1,3-dione (26.3 g, 99% yield) as a viscous liquid: 1H NMR (400 MHz, CDCl3) δ 7.76 (m, 2H), 7.67 (m, 2H), 4.25 (t, 2H, J=5.9 Hz), 3.77 (t, 2H, J=6.0 Hz), 1.91 (quintet, 2H, J=6.1 Hz), 0.82 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][N:6]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].COC(C)(C)C>O>[CH2:9]([N:6]1[CH2:7][CH2:8][CH:5]1[C:3]([OH:4])=[O:2])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C1CCN1Cc1ccccc1
Solvent: O
Solvent: COC(C)(C)C
Product: O=C(O)C1CCN1Cc1ccccc1
Temperature: 40 °C
Reaction time: 14 h

Procedure:
21.02 g of N-Benzylazetidine-2-carboxylic acid methyl ester, 592 g of t-butyl methyl ether and 40 g of water are mixed at 20 to 25° C. and then 1.41 g of enzyme (Chirazyme L-2) was added thereto and the resulting solution was heated to 40° C. and stirred for 14 hours. Settled solution was separated into an aqueous phase and an organic phase. The aqueous phase was washed twice with t-butyl methyl ether to yield an aqueous solution of optically active N-benzylazetidine-2-carboxylic acid and a combined organic phase of N-benzylazetidine-2-carboxylic acid methyl ester. Results of the same analysis as in the Example 1 is shown in Table 7.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O>>[CH3:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: Cc1ccc(C=O)c(C)c1
Product: Cc1ccc(C=C(C#N)C#N)c(C)c1

Procedure:
This material was prepared from malononitrile and 2,4-dimethylbenzaldehyde according to the procedure of M. Boehringer et al., WO 03/068748.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].Cl>C(#N)C>[CH2:12]([N:7]1[CH2:8][CH2:9][C:10]2[C:1](=[O:11])[NH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]ccc2cnccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1[nH]ccc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a suspension of 2,6-naphthyridin-1(2H)-one (2.04 g, 13.96 mmol) in acetonitrile (35 mL) was added benzylbromide (1.992 mL, 16.75 mmol). The mixture was heated to reflux. After 2 h the mixture was cooled to rt. The solvent was removed under reduced pressure and the residue was dissolved in EtOH (30 mL) and cooled to 0° C. Sodium borohydride (2.64 g, 69.8 mmol) was added portionwise over 30 min and the mixture was warmed to rt as the ice bath melted. After stirring the reaction mixture overnight at rt, the mixture was carefully acidified to pH=3 with 1N HCl and was stirred for 30 minutes at rt. The solution was concentrated under reduced pressure. The residue was neutralized with sat. aq. NaHCO3 and was extracted with dichloromethane (3×150 mL). The organic solution was concentrated under reduced pressure, and the residue was purified by BIOTAGE® flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give 6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (2.56 g, 10.65 mmol, 76% yield) as a light-yellow solid. LC/MS: m/z 241.08 (M+H)+, 1.362 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.29 (br. s., 1H) 7.31-7.37 (m, 4H) 7.24-7.30 (m, 1H) 7.12 (d, J=6.41 Hz, 1H) 5.89 (d, J=6.71 Hz, 1H) 3.63 (s, 2H) 3.32 (br. s., 2H) 2.62 (t, J=5.80 Hz, 2H) 2.40 (t, J=5.04 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]([OH:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1COCC1.C(OC(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 311, the title compound was synthesized using 6-bromo-3-(1-hydroxypropyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one. Crystals (THF-diisopropyl ether).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[CH3:23][N:24]1[C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][N:26]=[CH:25]1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH:31][CH2:30][CH2:29][C:28]4[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=4)=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:21][CH:20]=1
Reactant: Cn1cncc1CCN
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Product: Cn1cncc1CCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Yield: 31.8 %

Procedure:
The product was synthesized as described in Example 109 using 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (142.5 mg, 0.45 mmol) and 3-methylhistamine 100 mg, 0.5 mmol). The product was purified by semipreparative HPLC (20–80% acetonitrile gradient over 30 minutes at 20 mL/min) to yield the title compound (52 mg, 32% yield). 1H NMR (DMSO-d6) δ 8.85 (s, 1H), 8.5 (s, 1H), 8.05 (m, 2H), 7.9 (d, 1H), 7.7 (d, 1H), 7.4 (m, 3H), 3.9 (s, 3H), 3.6 (m, 2H), 3.0 (m, 2H). ES-MS m/z 364 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9](OC)OC.CON=[CH:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[C:24]=1[CH2:32][N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1.[NH4+].[OH-]>Cl>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[N:7][C:8]1[C:31]3[CH:30]=[C:26]4[O:27][CH2:28][O:29][C:25]4=[C:24]([CH2:32][N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)[C:23]=3[CH2:22][C:9]2=1
Reactant: COc1ccc(CNCC(OC)OC)cc1OC
Reactant: CON=Cc1ccc2c(c1CN1CCN(C)CC1)OCO2
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc2cnc3c(c2cc1OC)Cc1c-3cc2c(c1CN1CCN(C)CC1)OCO2
Temperature: 100 °C
Reaction time: 3 h
Yield: 3.5 %

Procedure:
The amine 8 (560.3 mg, 2.19 mmol) and oxime ether 13d (320.2 mg, 1.10 mmol) were mixed together with concentrated hydrochloric acid (10 mL) and the mixture was stirred at 100° C. for 3 h. The reaction mixture was then cooled and washed with ether (3×20 mL). It was then brought to basic pH with 28% aqueous NH4OH. The mixture was extracted with CHCl3 (3×40 mL), and the organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4 and concentrated. The residue was diluted in CHCl3 (40 mL) and filtered. Hydrochloric acid (2 M HCl in ether, 10 mL) was added to the filtrate. A dark yellow precipitate was obtained and recrystallized from methanol to provide a bright yellow solid. NH4OH (2 mL) was added to the yellow solid and the mixture was concentrated to dryness. The residue was purified by preparative flash chromatography (SiO2, methanol-chloroform-TEA=10:90:2) to yield the final pure product 14d as a yellow solid (16.7 mg, 3.5%): mp 296° C. (dec). IR 3400, 1489, 1455, 1245, 1159 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.98 (s, 1H), 7.47 (s, 1H), 7.24 (s, 1H), 7.08 (s, 1H), 6.04 (s, 2H), 4.11 (s, 3H), 4.04 (s, 3H), 3.91 (s, 2H), 3.68 (s, 2H), 2.65 (brs, 4H), 2.56 (brs, 4H), 2.34 (s, 3H); ESIMS m/z (rel intensity) 434 (MH+, 100), 334 (25). Anal. (C25H27N3O4.3.5H2O) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.CI.[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O.[OH-].[Na+]>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([O:12][CH3:17])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: Cc1cc(=O)oc2c(C)c(O)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(C)cc(=O)oc2c1C
Yield: 66 %

Procedure:
A solution of 4,8-dimethyl-7-hydroxycoumarin (0.190 g, 1.00 mmol) and methyl iodide (0.180 g, 1.30 mmol) in 50 ml of dry acetone was heated at reflux in the presence of 0.5 g of potassium carbonate for 14 hours. The solution was then cooled and filtered. The filtrate was evaporated under reduced pressure to yield a beige solid. The beige solid was taken up in 20% sodium hydroxide (aqueous) and collected by vacuum filtration. The crude product was recrystallized from methanol to yield shiny white crystals, m.p. 162°-164° C., 135 mg, 66% yield. 1H-NMR: 2.27 (s, 3H, C8 --CH3), 2.4 (d, 3H, C4 --CH3, J=1.2 Hz), 3.9 (s, 3H, OCH3), 6.1 (q, 1H, C3 --H, J=1.2 Hz), 6.8-6.9 (d, 1H, C6 --H, J=8.8 Hz), 7.4- 7.5 (d, 1H, C5 --H, J=8.8 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O)C.[H-].[Na+].O[NH:28][C:29](=[NH:31])[CH3:30].C(OCC)(=O)C>C1COCC1>[C:15]([O:14][C:12](=[O:13])[NH:11][C:9]1[S:10][C:6]([C:4]2[O:3][N:31]=[C:29]([CH3:30])[N:28]=2)=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=1)([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(=N)NO
Reactant: CCOC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(-c2sc(NC(=O)OC(C)(C)C)nc2-c2ccccc2)n1
Yield: 36 %

Procedure:
2-Tert-butoxycarbonylamino-4-phenyl-thiazole-5-carboxylic acid ethyl ester (1.9 g 5.6 mmol) was dissolved in dry THF (60 mL). Sodium hydride (60% in oil) and N-hydroxy-acetamidine (0.83 g, 11.2 mmol) dissolved in THF (30 mL) was added. The reaction mixture was heated to reflux over night. The reaction mixture was cooled and ethyl acetate (75 mL) glacial acetic acid (0.43 g) were added. The organic mixture was washed with brine (75 mL). The aqueous phase was extracted with ethylacetate The combined organic phases was washed with brine (50 mL) dried with MgSO4 and solvents were removed in vacuo to give a solid. Yield: 36%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[CH3:23][C:4]1[CH:3]=[C:2]([NH2:24])[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1cccc(C)c1
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1cccc(C)c1

Procedure:
In an analogous manner to that described in Example 4)) from 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-3-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(toluene-3-sulphonyl)-pyrazolo[1,5-a]pyrimidine-7-ylamine as colorless crystals, m.p.>2500.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.S(=O)(=O)(O)O.[C:15]([O-])(O)=O.[Na+]>CO>[OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH3:15])=[O:8])[CH2:5][CH2:4]1
Reactant: O=C([O-])O
Reactant: O=C(O)CC1(CO)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 g 2-[1-(hydroxymethyl)cyclopropyl]acetic acid (compound (13)) was dissolved in 65 ml methanol and 80 mg sulfuric acid was added. The reaction mixture was stirred overnight at room temperature; reaction progress was monitored by GC. The pH of the reaction mixture was adjusted to 7 with saturated NaHCO3. The reaction mixture was evaporated to dryness. 75 ml of ethyl acetate and 10 ml brine were added. The water layer was washed with 20 ml ethyl acetate. The combined organic layers were dried (Na2SO4) and evaporated to dryness, resulting in a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25](O)[CH2:26][OH:27]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]1[O:27][CH2:26][CH2:25][O:6]1
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1C1OCCO1
Temperature: 50 °C
Reaction time: 12 h
Yield: 95.5 %

Procedure:
To a stirred solution of 2-methoxy-4-nitro-benzaldehyde (4.61 g, 25.4 mmol) in toluene (51 mL), was added p-toluene sulfonic acid (483 mg, 2.54 mmol), followed by ethylene glycol (2.83 mL, 50.8 mmol). After heating the reaction mixture at 50° C. for 12 h, additional p-toluene sulfonic acid (483 mg, 2.54 mmol) and ethylene glycol (2.83 mL, 50.8 mmol) were added. After an additional 12 h, the solvent was removed under reduced pressure, and the resulting residue was dissolved in dichloromethane (50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (25 mL), dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound as a yellow solid (5.46 g, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.CCOC(C)=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: BrCCc1ccccc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccn(CCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-nitro-1H-pyrazole (226 mg, 2.0 mmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (0.33 g, 2.4 mmol) and 1-bromo-2-phenylethane (0.44 g, 2.4 mmol). The resulting mixture was stirred at rt overnight. TLC showed the reaction was complete. The mixture was diluted with EtOAc (40 mL), then washed with water (2×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. The crude material was purified by chromatography on silica gel, eluting with Hex:EtOAc=80:20→70:30 to give the title compound as a white solid. NOE experiment confirmed the structure. 1H NMR (CDCl3, 400 MHz): δ=3.22 (t, J=7.1 Hz, 2H), 4.43 (t, J=7.1 Hz, 2H), 6.79 (d, J=2.5 Hz, 1H), 7.06-7.09 (m, 2H), 7.12 (d, J=2.5 Hz, 1H), 7.23-7.32 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:32]([F:33])=[CH:31][C:30]([C:34]3[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=3)=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:40])=[CH:18][N:17]=1>>[Cl:40][C:19]1[C:20]([NH:22][C:23]2[C:32]([F:33])=[CH:31][C:30]([C:34]3[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=3)=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCCOc2ccc(N)cc21
Product: CCN1CCCOc2ccc(Nc3ncc(Cl)c(Nc4c(F)cc(-c5cnn(C)c5)cc4C(=O)NC)n3)cc21

Procedure:
2-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide was prepared from 9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 1410. Product isolated as a white solid (58 mg, 30%). m.p.=253-255° C.; LCMS (m/e) 551 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.20 (s, 1H), 8.99 (s, 1H), 8.56-8.50 (m, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.74-7.64 (m, 2H), 7.01 (d, 1H, J=9.6 Hz), 6.89 (s, 1H), 6.50 (d, 1H, J=8.6 Hz), 3.95-3.85 (m, 5H), 3.12-2.96 (m, 4H), 2.75 (d, 3H, J=4.5 Hz), 1.87-1.78 (m, 2H), 1.05 (t, 3H, J=7.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:43][CH2:44][C:45]1[CH:46]=[C:47]([CH:62]=[CH:63][CH:64]=1)[C:48]([NH:50][C:51]1[CH:60]=[C:59]2[C:54]([CH2:55][CH2:56][N:57]([CH3:61])[CH2:58]2)=[CH:53][CH:52]=1)=[O:49].CN1CCOCC1>CN(C=O)C>[CH3:61][N:57]1[CH2:56][CH2:55][C:54]2[C:59](=[CH:60][C:51]([NH:50][C:48]([C:47]3[CH:46]=[C:45]([CH:64]=[CH:63][CH:62]=3)[CH2:44][NH:43][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=4)=[CH:13][CH:12]=3)=[O:16])=[O:49])=[CH:52][CH:53]=2)[CH2:58]1
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Reactant: O=C(O)c1ccc(-c2cccc(O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(-c5cccc(O)c5)cc4)c3)cc2C1

Procedure:
To a vial containing 3′-hydroxy-biphenyl-4-carboxylic acid (26 mg, 0.12 mmol) add a solution of HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate) (57 mg, 0.15 mmol) in DMF (1 mL) followed by a solution of 3-aminomethyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide dihydrochloride (37 mg, 0.10 mmol) and 4-methylmorpholine (0.044 mL, 0.40 mmol) in DMF (1 mL). Shake the reaction at rt for 24 h. Concentrate in vacuo to an oil. Dissolve the residue in 10% water in DMSO (0.9 mL) and purify by prep-HPLC (10% to 90%, CH3CN/H2O). Concentrate fractions to afford the desired product 3′-hydroxy-biphenyl-4-carboxylic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide as a solid in 45% yield (22 mg, 0.045 mmol). MS, electrospray (M+H) 492.4, rt 2.29 min.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[Cl:5][C:6]1[C:7]([NH2:13])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:5][C:6]1[C:7]([N:13]=[C:1]=[S:2])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: S=C=Nc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
Thiophosgene (21.9 ml, 288 mmol) was added dropwise to a stirred mixture of 3,5-dichloropyridin-2-amine (23.5 g, 144 mmol) in tetrahydrofuran (150 mL) and saturated aqueous sodium hydrogen carbonate (150 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (11.4 g, 55.6 mmol, 39%).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:20][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][N:25]=2)[CH3:22])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(C(F)(F)F)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 86.8 %

Procedure:
To a solution of 2-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-trifluoromethyl-pyridine 0.45 g (0.91 mmol) dissolved in toluene (5 mL) were added 0.30 mL (2.7 mmol) of 1-chloroethyl chloroformate and 0.46 mL of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (5 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 0.32 g (87%) of the title compound as a light yellow oil. ES-MS m/e: 405.9 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([NH:36][CH2:37][CH2:38][OH:39])[CH3:35]>>[CH2:34]([N:36]([CH2:37][CH2:38][OH:39])[C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[CH3:35]
Reactant: CCNCCO
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCN(CCO)C(=N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Yield: 7 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.1 equivalents of 2-(ethylamino)ethanol as secondary amine. The product was purified by preparative HPLC.