Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[C:6]=2[C:5]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:6]=2[C:5]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2ccc(Cl)cc2Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CCCCO)c12
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-{4-chloro-2-[(2,4-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}butanoate (Reference Example 34; 453 mg, 0.920 mmol) in tetrahydrofuran (5 mL) was added lithium borohydride (60 mg, 2.76 mmol), and the mixture was refluxed for 2 hr. After cooled to room temperature, the reaction mixture was quenched with methanol (0.5 mL) and concentrated to dryness. The residue was partitioned between ethyl acetate (10 mL) and water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL×3), washed with brine (15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-{4-chloro-2-[(2,4-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}butan-1-ol, which was subjected for example without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(O)(C(F)(F)F)=[O:14]>[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([OH:14])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cnc2ccccc2c1
Agent: O=[Pt]
Product: COc1cnc2c(c1)CCCC2O
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 3-methoxyquinoline (1.06 g, 6.7 mmol) in TFA (22 mL) under nitrogen was added platinum oxide (225 mg, 1.3 mmol) and the suspension bubbled with hydrogen gas 16 h at 60° C. The mixture was then cooled to room temperature, neutralized to pH 12 with 10 N NaOH and extracted with CH2Cl2 (3×50 mL). The organic extracts were dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (ethyl acetate/hexane; 1:2) to give the desired 3-methoxy-5,6,7,8-tetrahydroquinoline (0.95 g, 87%). 1H NMR (CDCl3) δ 1.77 (m, 2H), 1.85 (m, 2H), 2.75 (t, 2H, J=6.0 Hz), 2.85 (t, 2H, J=6.0 Hz), 3.81 (s, 3H), 6.88 (d, 1H, J=1.5 Hz), 8.07 (d, 1H, J=1.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=1.[CH2:26](Br)[CH:27]=[CH2:28].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:28]([N:4]1[C:3](=[O:25])[C:2]([Cl:1])=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=2)[C:6]([N+:22]([O-:24])=[O:23])=[N:5]1)[CH:27]=[CH2:26]
Reactant: CCCOc1cc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)ccc1OC
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCn1nc([N+](=O)[O-])c(NCc2ccc(OC)c(OCCC)c2)c(Cl)c1=O
Reaction time: 1.5 h

Procedure:
A mixture comprising 500 mg of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, 820 mg of allyl bromide, 937 mg of anhydrous potassium carbonate and 25 ml of methyl ethyl ketone, was refluxed under stirring for 1.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue thereby obtained, the mixture was extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography by using a solvent mixture of benzene: ethyl acetate (85:15 v/v) as the eluent, to obtain 394 mg of the above identified compound having a melting point of from 62.5° to 64° C. as yellow crystals.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11](O)([CH3:13])[CH3:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH2:12]=[C:11]([CH:8]1[CH2:7][CH2:6][C:5]2([O:1][CH2:2][CH2:3][O:4]2)[CH2:10][CH2:9]1)[CH3:13]
Reactant: CC(C)(O)C1CCC2(CC1)OCCO2
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: C=C(C)C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution 2-(1,4-dioxaspiro[4.5]decan-8-yl)propan-2-ol (164 mg, 0.82 mmol, prepared in the Example 29, Step A) in THF (10 mL) cooled to 0° C. under argon was added Burgess Reagent (214 mg, 0.87 mmol). After the complete addition, the reaction mixture was at room temperature 1 hour and then concentrated in vacuo. The residue purified by flash chromatography (silica gel, DCM) to afford the product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24]C(OC(C)(C)C)=O)[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(OC2CCN(C(=O)OCc3ccccc3)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(OC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
4-(3-tert-Butoxycarbonylamino-phenoxy)-piperidine-1-carboxylic acid benzyl ester (11.8 g, 27.6 mmol) is dissolved in a solution of trifluoroacetic acid in dichloromethane (25% v/v, 20 mL). The reaction mixture is stirred at 22° C. for 60 min. After removal of the solvent, the oily residue is dissolved in dichloromethane (250 mL) and neutralized with 0.2 N aqueous sodium hydroxide solution (250 mL) and extracted with dichloromethane (10×100 mL) followed by ethyl acetate (5×100 mL). The combined organic phases are dried over anhydrous sodium sulfate. After removal of solvent, the crude product is purified on silica gel chromatography with dichloromethane-methanol to give a light brown oil (4.84 g, 54%, ES+(m/z) 327.3 [M+H]).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22].[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[CH2:2][C:25]1[CH:26]=[CH:27][S:23][CH:24]=1)[O:10][CH:9]([C:13]([F:16])([F:15])[F:14])[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Cc3ccsc3)cc2OC1C(F)(F)F
Temperature: 65 °C

Procedure:
The ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (2.0 g, 5.0 mmole) was dissolved in DME (10.8 mL). The thien-3-ylboronic acid (127.96 mg, 5.0 mmole) was added to above solution and followed by addition of Pd(PPh3)4 (40 mg). After addition of 2M Na2CO3 (5.0 mL), the reaction was heated to 60-70° C. The color of the reaction changed from yellow to red and back to yellow. The solution was heated to reflux for 2 hrs. Additional 107 mg of thien-3-ylboronic acid and Pd(PPh3)4 (8 mg) were added to above mixture. After 2 hsr, the reaction was diluted with 5 ml of water and extracted with EtOAc. The organic layer was washed with NaHCO3 (sat.) and dried over MgSO4 and filtered. The filtrate was concentrated to afford the title ester. The ester (dark oil) was purified by chromatography eluted with 5 to 10% EtOAc in Hexane to give 620 mg, which had suitable purity to use without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:11]12[CH2:17][CH:14]([CH:15]=[CH:16]1)[CH2:13][CH:12]2[C:18](Cl)=[O:19])[CH:9]=[CH2:10]>>[C:2]1([NH:1][C:18]([CH:12]2[CH2:13][CH:14]3[CH2:17][C:11]2([CH2:8][CH:9]=[CH2:10])[CH:16]=[CH:15]3)=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC12C=CC(CC1C(=O)Cl)C2
Reactant: Nc1ccccc1
Product: C=CCC12C=CC(CC1C(=O)Nc1ccccc1)C2

Procedure:
20.5 g of aniline and 39.3 g of allylbicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are reacted in accordance with process A, affording 40.6 g (80.3% of theory) of a brown resin which is solid at room temperature and has a softening point of 66° C. The IR spectrum shows a band at 3300 cm-1 (--NH--) und at 1660 cm-1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cc(Cl)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cc(Cl)ccc1Br
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of 2-(2-bromo-5-chloro-phenyl)ethanol (1.65 g, 7.00 mmol) [as prepared in preparation 6] and triethylamine (922 mg, 1.27 mL, 9.11 mmol) in DCM (20 mL) was cooled to 0° C. and methanesulfonyl chloride (883 mg, 597 μL, 7.71 mmol) was added. The mixture was stirred for 2 h and then diluted with DCM and washed sequentially with water and brine, the organic layer dried (MgSO4) and concentrated to afford 2-bromo-5-chlorophenethyl methanesulfonate as a yellow solid (2.11 g, 96%). 1H NMR (500 MHz, d6-DMSO) δ 7.67 (1H, d), 7.55 (1H, s), 7.32 (1H, d), 4.44 (2H, t), 3.13-3.36 (5H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][C:11]([F:25])=[C:12]([Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])(=O)C.[K+]>C(O)C.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:25][C:11]1[N:10]=[C:9]2[O:8][C:5]3[C:4]([C:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]2=[CH:13][C:12]=1[Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:3][C:2]([C:32]1[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: C[Si](C)(C)c1cc2c(nc1F)Oc1ccc(Br)cc1C21COC(N)=N1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)c1cc2c(nc1F)Oc1ccc(-c3cccnc3F)cc1C21COC(N)=N1
Temperature: 80 °C

Procedure:
7-Bromo-2-fluoro-3-(trimethylsilyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.137 g, 0.324 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ii) (0.011 g, 0.016 mmol), 2-fluoropyridin-3-ylboronic acid (0.055 g, 0.389 mmol), and potassium acetate (0.127 g, 1.298 mmol) were suspended in a mixture of ethanol (30 mL) and water (5 mL) and heated to 80° C. After 20 minutes the solution was cooled to rt and concentrated under reduced pressure to ˜10 mL. This solution was then diluted with water (100 mL) and EtOAc (100 mL). The phases were mixed and separated and the organics were dried with magnesium sulfate before filtered and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% methanol in DCM gradient followed by a second column using dichloromethane to EtOAc gradient) gave the desired 2-fluoro-7-(2-fluoropyridin-3-yl)-3-(trimethylsilyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH2:28][C:29]1([OH:37])[CH:34]2[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]2)[CH2:30]1.CN(C)C=O>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:27][CH2:28][C:29]1([OH:37])[CH:34]2[CH2:33][CH2:32][N:31]([CH2:36][CH2:35]2)[CH2:30]1)=[O:9]
Reactant: NCC1(O)CN2CCC1CC2
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNc1cc(OC)c(C(=O)NCC2(O)CN3CCC2CC3)cc1Cl
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of 5-chloro-2-methoxy-4-(methylamino)benzoic acid (3.02 g, 0.014 mole) in anhydrous tetrahydrofuran (15 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (2.35 g, 0.0145 mole) and stirred for one hour. A solution/suspension of 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol (2.34 g, 15 mole) in tetrahydrofuran (15 ml) containing a little N,N-dimethylformamide for solubility was added slowly over a few minutes, and the mixture was stirred overnight (18 hours) at room temperature and for one hour at 60° C., then concentrated in vacuo. The white solid was partitioned between 1.0N sodium carbonate (100 ml) and methylene chloride (200 ml) containing a little methanol, and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 ml) containing a little methanol, and the combined organic solution was dried (sodium sulfate) and passed through a short column of alumina (eluted with 10% methanol/methylene chloride). The filtrate was concentrated in vacuo, triturated from ether, and triturated from acetonitrile to afford 2.67 g (54%) of the title compound as a colorless solid; mp 236°-237° C. (dec).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].S(Cl)(Cl)=O.[CH3:25][C@H:26]1[CH2:31][C@@H:30](O)[C@H:29]([CH:33]([CH3:35])[CH3:34])[CH2:28][CH2:27]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:20][C:26]1([CH3:25])[CH2:31][CH2:30][CH:29]([CH:33]([CH3:35])[CH3:34])[CH2:28][CH2:27]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)CCCCCCCCCCCCCCC(=O)OC1(C)CCC(C(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.1 %

Procedure:
284.5 g of isostearic acid (molecular weight: 284.49, 1.00 mol) and thionyl chloride (molecular weight: 118.97, 1.05 mol) were placed in a 1-L reaction flask equipped with a thermometer. The mixture was stirred at room temperature for 20 minutes and then, heated at an oil bath temperature of 40° C. and stirred for 1 hour. The reaction solution obtained was left under reduced pressure for removal of the dissolved gas and excess thionyl chloride. 300 ml of toluene and 156.3 g of 1-menthol (molecular weight: 156.27, 1.00 mol) were added thereto; and 121.4 g of triethylamine (molecular weight: 101.19, 1.20 mol) was added dropwise over 20 minutes. After dropwise addition, the mixture was stirred at an oil bath temperature of 60° C. for 3 hours. The reaction solution obtained was quenched in water and extracted with toluene. The toluene phase was washed with aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and condensed in rotary evaporator for removal of the solvent to give yellow oil. Distillation thereof under reduced pressure gave a desired product, isostearic acid-1-menthyl as colorless oil. Yield: 351.4 g, (molecular weight: 422.7, 831.4 mmol), purity: 99.8%, yield: 83.1%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].[N:41]1([CH2:46][CH2:47][NH2:48])[CH2:45][CH2:44][CH2:43][CH2:42]1>>[N:41]1([CH2:46][CH2:47][NH:48][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:15]3[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[CH:9]3[CH:8]4[CH2:34][C:35]5[C:40]([CH:7]4[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=4)[NH:10]3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:24]([O:32][CH3:33])[CH:25]=2)=[O:30])[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Reactant: NCCN1CCCC1
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCCN3CCCC3)cc2OC)cc1O

Procedure:
Example 240 was prepared according to the protocol described for example 235 from 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (example 235 step a) and 2-pyrrolidin-1-yl-ethylamine. Mass Spectrum: 632 (M+1).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([CH3:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=C[CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([CH3:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][CH:44]5[CH2:43][N:48]([CH3:47])[CH2:45]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(C)(F)C(=O)N2C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(C)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (m, 2H) 1.62-2.06 (m, 14H), 2.29 (s, 1H) 2.50 (s, 3H) 3.25 (t, J=6.3 Hz, 2H) 3.47 (s, 3H) 3.80 (t, J=6.6 Hz, 2H) 3.88-4.09 (m, 2H) 4.16 (s, 3H) 4.52-4.77 (m, 1H) 7.70 (d, J=8.3 Hz, 1H) 8.00 (s, 1H). [M+H] calc'd for C27H36FN7O3, 526. found 526.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([OH:13])[CH:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9]2)=[C:4]([N+:29]([O-:31])=[O:30])[CH:3]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH:10]3[CH2:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[N+:29]([O-:31])=[O:30])[CH2:12][CH:11]3[O:13][C:39](=[O:41])[CH3:40])[CH2:19][CH2:18]2)=[O:21])=[CH:23][CH:24]=1
Reactant: CC(=O)Cl
Reactant: O=C(c1ccc(Cl)cc1)N1CCN(C2CN(c3ccc(Cl)cc3[N+](=O)[O-])CC2O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1CN(c2ccc(Cl)cc2[N+](=O)[O-])CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of {4-[1-(4-chloro-2-nitro-phenyl)-4-hydroxy-pyrrolidin-3-yl]-piperazin-1-yl}-(4-chloro-phenyl)-methanone (300 mg, 0.64 mmol) in CH2Cl2 (5 mL) at 0° C., was added Et3N (0.2 mL, 1.42 mmol) and acetyl chloride (112 mg, 1.42 mmol). The mixture was stirred at RT for overnight. The organic phase was washed with Saturated NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate) to give the desired product (160 mg, 50% yield) as a yellow oil. MS: (ESI), M/Z, 507 (M+1). Retention time: 2.59 min (FA-polar).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:8]1[CH2:9][CH2:10][N:11](CC2C=CC=CC=2)[CH2:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:7])([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)C1CCNCC1
Reaction time: 20 h

Procedure:
2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propionic acid ethyl ester from above (1.15 g, 4.0 mmol) was dissolved in 50 mL of ethanol and 10% palladium on carbon (600 mg) was added. The mixture was hydrogenated at 50 psi for 20 hrs. The mixture was filtered and solvents were evaporated to give 2-methyl-2-piperidin-4-yl-propionic acid ethyl ester (760 mg) as an oil. The NMR spectrum obtained on the sample is compatible with its structure. LRMS calcd for C11H21NO2 (m/e) 199.29, obsd 200.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:28]C(=O)OC(C)(C)C)[N:16]=[CH:15]2.Cl>O1CCOCC1.ClCCl>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[NH2:28])[N:16]=[CH:15]2
Reactant: CCOc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4N)ncc3c2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl ((1S,2R)-2-((6-(2-chloro-3-ethoxy-6-fluorophenyl)quinazolin-2-yl)amino)cyclopentyl)carbamate (51 mg, 0.1 mmol) and 4M HCl in Dioxane (0.5 mL) in dichloromethane (1 mL) was stirred at room temperature for 2 h. LC-MS indicated complete consumption of SM. The reaction mixture was concentrated and used without further purification in the next step.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.[CH3:24]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:9]=3[N:10]([CH3:24])[C:11]=2[CH:12]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)ccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Sodium hydride (60% weight dispersion in mineral oil, 4.19 g, 0.105 mol) was added portionwise to a solution of tert-butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (23.6 g, 0.07 mol) in DMF (300 mL) at room temperature under N2. After 1 h, methyl iodide (14.8 g, 6.47 mL, 0.105 mol) was added, and the reaction was allowed to proceed for an additional 2 h. The mixture was quenched with H2O, upon which a solid precipitated out of solution. The suspension was therefore diluted to 2 L with H2O and filtered. The solids were washed thoroughly with water, then dissolved in CH2Cl2, dried over Na2SO4, filtered and concentrated to dryness. This provided the title compound (22.4 g, 91%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 4.60 (s, 2H), 3.81 (br t, 2H), 3.58 (s, 3H), 2.77 (t, J=5.4 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:9].[Na+].S(=O)(=O)(O)O.I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[Cl:9][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[O:7][CH3:8]
Reactant: [Cl-]
Reactant: COc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1Cl
Temperature: 80 °C
Yield: 2 %

Procedure:
Anisole (1 mmol) was treated with sodium chloride (1.2 mmol) in acetonitrile: water (2:1, 6 ml). 20% Sulfuric acid (5 ml) and sodium periodate (20 mol %) was added to reaction mixture. The mixture was heated at 80° C. under inert atmosphere for 4 h. The product was purified by column chromatography to give 4-chloroanosole (25%) and 2-chloroanisole (2%).