Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[C:25][CH2:26][OH:27])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:28].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([O:27][CH2:26][C:25]#[C:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:29]=[CH:30][CH:31]=[C:2]([F:1])[CH:3]=2)=[C:8]([Cl:28])[CH:9]=1)(=[O:42])=[O:41]
Reactant: OCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 3-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)prop-2-yn-1-ol (compound 10.1, 800 mg), triethyl amine (0.4 mL) in dichloromethane (20 mL) at 0° C. was added MsCl (0.16 mL) and the reaction mixture was warmed to room temperature. The reaction was washed with saturated NaHCO3 aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with EtOAc to give the desired product. LCMS ESI(+) m/z: 513 (M+1). Yield: 43%.
Reaction SMILES: [CH2:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[CH2:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][C:10]2[C:11](=[O:12])[NH:13][C:17](=[O:18])[C:16]=2[OH:22])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)Cc1ccc(OCC(N)=O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Cc1ccc(OC2=C(O)C(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-acetonylphenoxyacetamide, ethylene ketal (3.2 g) and diethyl oxalate (2.0 g) in dry dimethylformamide at 0° C. was treated with potassium tert-butoxide (3.24 g) in two portions at 15 min. intervals. The solution was then stirred 16 h at ambient temperature, poured into water, and acidified with 6N hydrochloric acid. The aqueous solution was extracted with ethyl acetate, the combined organic extracts dried (magnesium sulphate), filtered and evaporated and the residue crystallised from acetone/ether to give 4-[4-acetonylphenoxy]-3-hydroxy-1H-pyrrole-2,5-dione, (1.5 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][OH:17])[C@@H:7]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2].O[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][O:17][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C@@H:7]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: Oc1cccnc1
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCO)C2=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCOc1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans tert-butyl 8-ethyl-4-(2-hydroxyethyl)-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, from Example 86, Part B, (24 mg, 0.064 mmol) in 1 mL of toluene was added 3-hydroxypyridine (9 mg, 0.096 mmol), triphenylphosphine (20 mg, 0.077 mmol) and diethylazodicarboxylate (0.035 mL, 0.077 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was diluted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:2 to 1:2 hexane/ethyl acetate) to afford 20 mg of the title compound which was contaminated with a small amount of triphenylphosphine oxide. LRMS (ESI): 452.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH2:16]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34]Cl)[CH2:29][C@@H:28]1[C:36]([O:38][CH3:39])=[O:37])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC1C(F)=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>>[CH2:16]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[CH2:29][C@@H:28]1[C:36]([O:38][CH3:39])=[O:37])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Reactant: COC(=O)[C@H]1CN(CCCl)CC[C@H]1NC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)c(F)c32)CC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (350 mg, 1.93 mmol) was deprotonated with sodium hydride (85 mg, 60% in oil, 2.13 mmol) and alkylated with methyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-chloroethyl)piperidine-3-carboxylate (Intermediate 36) (1.93 mmol) as described for Intermediate 20. Colorless hard foam, 604 mg (63%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH2:14]([N:17]([CH2:25][C:26](N(OC)C)=[O:27])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH2:16].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:14]([N:17]([CH2:25][C:26]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:27])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:15]=[CH2:16]
Reactant: Fc1ccc(Br)nc1
Reactant: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCN(CC(=O)c1ccc(F)cn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 32.8 %

Procedure:
2-Bromo-5-fluoro-pyridine (2.46 g, 13.98 mmol) in tetrahydrofuran (20 mL) is added drop wise to isopropylmagnesium chloride (15 mL, 30.00 mmol of a 2M solution in tetrahydrofuran) with stirring under nitrogen at room temperature. The resulting reaction mixture is stirred at room temperature for 2 hours. tert-Butyl N-allyl-N-[2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (3.4 g, 13.16 mmol) in tetrahydrofuran (15 mL) is then added drop wise at room temperature and the resulting mixture is stirred overnight. Dilute aqueous hydrochloric acid is added followed by ethyl acetate. The layers are separated and the aqueous phase is re-extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue is purified by silica gel column chromatography using a 0-40% gradient of acetone in iso-hexane to give the title compound (1.27 g, 33%). ES/MS (m/e): 317 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CO)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCl)cc1
Yield: 81.5 %

Procedure:
To a solution of p-methoxycarbonylbenzyl alcohol (332.0 g, 2.0 mol) in methylene chloride (600 mL) is added thionyl chloride (380 g, 3.2 mol) dropwise over 3 hours and the reaction mixture heated at gentle reflux for 6 hours, allowing excess gases to escape. The excess thionyl chloride and methylene chloride are removed and the yellow oil triturated with hexane to yield a total of 300 g (81.5% yield) of white, solid methyl α-chloro-p-toluate, the identity of which is confirmed by elemental analysis and mass spectrum analysis as follows:
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[Br:11]Br>CO>[CH:4]1([C:2]([CH2:1][Br:11])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: BrBr
Reactant: CC(=O)C1CCCCCC1
Solvent: CO
Product: O=C(CBr)C1CCCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
An ice cold solution of 19.0 g of cycloheptyl methyl ketone in 100 ml of methyl alcohol was treated dropwise with 7 ml of bromine. After 5 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then diluted with 500 ml of water and extracted with ethyl ether (3×75 ml). The combined extracts were washed with saturated sodium bicarbonate, brine, dried (MgSO4) and condensed in vacuo to yield 29.9 g of bromomethyl cycloheptyl ketone as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CS(C)=O.Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O>[CH2:36]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: Oc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCOc1ccccc1-c1ccccc1
Temperature: 70 °C
Reaction time: 7.5 h

Procedure:
A 100 mL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser, a nitrogen blanket, and a heating mantle with a temperature controller and a thermocouple. The flask was charged with o-phenylphenol (3.42 grams, 0.02 moles), with KOH pellets (1.37 grams, 0.02 moles, 85%), and with 15 mL of DMSO. The mixture was stirred at 100° C. under nitrogen until all of the KOH had dissolved (about 2 hours). The dark solution was cooled to 70° C., then the 1-chlorohexadecane (5.22 grams, 0.02 moles) was then added all at once. An exotherm to about 80° C. was observed. The reaction mixture was then stirred at 75° C. for about 7.5 hours, then it was poured into about 500 mL of water; solids separated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccc(C#N)o2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1ccc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-(5-cyano-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 347 ([M—H]−, 100).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@@H:6]2[CH2:13][N:14]([C:16](OC(C)(C)C)=O)[CH2:15][C@H:5]2[CH2:4][NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:16][N:14]1[CH2:15][C@@H:5]2[C@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:2][NH:3][CH2:4]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC(=O)c3ccccc3[C@@H]2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C[C@H]2CNCc3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Example 71A (2.62 g, 8.66 mmol) in tetrahydrofuran (87 mL) was added lithium aluminum hydride in tetrahydrofuran (13.00 mL, 26.0 mmol) in small portions, and the mixture was stirred at room temperature for 24 hours. Water was added carefully and the product was extracted once with dichloromethane, dried over Na2SO4 and concentrated to afford the title compound. 1H NMR (500 MHz, pyridine-d5) δ ppm 7.31 (d, J=7.4, 1H), 7.20-7.17 (m, 2H), 7.13 (d, J=7.7, 1H), 4.58 (dd, J=14.5, 48.4, 2H), 4.01-3.90 (m, 2H), 3.71-3.57 (m, 2H), 3.40 (t, J=10.4, 1H), 3.19-3.05 (m, 2H), 2.71 (s, 3H), 2.66-2.52 (m, 1H); MS (ESI+) m/z 203.0 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH2:32][CH2:33][CH3:34])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:38](C1CCCN1)CC>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH2:32][CH:33]([CH3:38])[CH3:34])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCCC1CCCN1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5CC(C)C)c4)cc23)CC1
Yield: 21.6 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting 2-(2-methylpropyl)pyrrolidine (127 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 12.0 mg of the title compound (21.6%).
Reaction SMILES: [N+:1]([CH:4]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:5])([O-])=O.O1CCNC1>[Ni].CO>[NH2:1][CH:4]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:5]
Reactant: CCCCC(O)C(C)[N+](=O)[O-]
Agent: [Ni]
Agent: C1COCN1
Solvent: CO
Product: CCCCC(O)C(C)N
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Catalytic hydrogenation of the 2-nitro-3-heptanol to the 2-amino-3-heptanol alkanolamine. A sample of 2-amino-3-heptanol (2A3H) was synthesized by the reduction of the 2-nitro-3-heptanol by a Parr Autoclave unit. The stainless steel, 2 liter autoclave was loaded with Grace 3201 Raney Nickel (RaNi, 90 g wet, 45 g dry, 9 wt %) and methanol (MeOH, 300 g). The autoclave was sealed, assembled, purged with nitrogen then hydrogen, pressurized with hydrogen (600 psig), stirred at 600 RPM, and warmed to 40° C. The nitro-alcohol (491 g) was diluted with absolute ethanol (EtOH, 150 g) and pumped into the autoclave (4 ml/min) After 3 h the addition was complete and after 3.5 h the reaction was judged complete as no hydrogen uptake was observed. The autoclave was cooled, stirring stopped, vented, and purged with nitrogen. The autoclave was disassembled and the contents were vacuumed filtered to remove the RaNi catalyst. This resulted in the isolation of a yellow liquid (82 area %) that was concentrated in vacuo (55° C./full vacuum) before product was taken overhead (40-50° C./full vacuum). This resulted in the isolation of a clear, colorless, solid (302 g, 91.2 area %, 64% overall yield) that contained some oxazolidine (3.4 area %).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]3[CH2:26][CH2:25][N:24]([C:27](=[O:31])[CH2:28][O:29][CH3:30])[CH2:23]3)[C:7]=2[C:6]=1[CH3:33])=O.[NH3:34]>CO>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:33])=[C:5]([C:3]([NH2:34])=[O:2])[S:32][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][N:24]([C:27](=[O:31])[CH2:28][O:29][CH3:30])[CH2:23]2)[CH:16]=1
Reactant: COCC(=O)N1CCC(Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)OC)c(C)c23)C1
Reactant: N
Solvent: CO
Product: COCC(=O)N1CCC(Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 1.4 from 4-{4-fluoro-2-[1-(2-methoxy-acetyl)-pyrrolidin-3-yloxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and ammonia in methanol.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[N+:11]([O-])([OH:13])=[O:12].O>C(O)(=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc([N+](=O)[O-])ccc1O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of 2-isopropylphenol (4.1 ml) in acetic acid (30 ml) was added 69% nitric acid (4 ml) in an ice bath and the mixture was stirred at the same temperature for 30 minutes. After addition of iced water, the reaction mixture was extracted with t-butyl methyl ether. The extractant was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as an eluant to give the desired compound (2.66 g, yield 49%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:23]I>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:20][CH3:23])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the ester from step (a) above (4.3 g, 15.5 mol) in DMF (30 mL) was added NaH (60% in mineral oil, 0.93 g, 23.2 mmol) and the mixture was stirred at 0° C. for 1 h. MeI (1.16 mL, 18.6 mmol, Aldrich) was added drop-wise with stirring at 0° C., and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (50 mL), washed with saturated solution of NH4Cl (25 mL) and brine (25 mL), dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 10% EtOAc/hexane, to give the title compound as a light-yellow oil, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 292 (M+1).
Reaction SMILES: [C:1]([Cl:4])(=O)C.Cl.[C:6]([C@H:9]1[CH2:18][C@H:17]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=2)=[O:21])[C:16]2[C:11](=[CH:12][C:13]([Cl:31])=[CH:14][C:15]=2[Cl:30])[NH:10]1)([OH:8])=[O:7]>CO.Cl.CO>[ClH:4].[ClH:30].[CH3:1][O:7][C:6]([C@H:9]1[CH2:18][C@H:17]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=2)=[O:21])[C:16]2[C:11](=[CH:12][C:13]([Cl:31])=[CH:14][C:15]=2[Cl:30])[NH:10]1)=[O:8]
Reactant: CC(=O)Cl
Reactant: NCc1cccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2cccc(CN)c2)c2c(Cl)cc(Cl)cc2N1
Reaction time: 2 h

Procedure:
A solution of hydrogen chloride in methanol was prepared by the cautious addition of acetyl chloride (6 ml) to ice-cooled methanol (25 ml). Trans-2-carboxy-5,7-dichloro-4-(3-aminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline hydrochloride (87 mg, 0.202 mmol) (Example 81) was dissolved in the HCl/methanol solution and the resulting mixture was stirred in a stoppered flask for 2 h. The methanol and excess hydrogen chloride were removed in vacuo and the product recrystallised from methanol/ether to give the title compound as a colourless crystalline solid (80 mg) m.p. 173° C. (dec). δ (DMSO, 360 MHz) 1.94 (1H, ddd, J=13.7, 13.4 and 3.8 Hz, CHACHBHCCHD), 2.51 (1H, dm J=13.7 Hz, CHACHBHCCHD), 3.81 (3H, s, CH3), 4.10 (1H, dd, J=12.6 and 2.7 Hz, CHACHBHCCHD), 4.23 (2H, s, CH2NH2), 5.36 (1H, m, CHACHBHCCHD), 6.81 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.56 (1H, t, J=7.7 Hz, Ar-H), 7.65 (1H, d, J=7.8 Hz, Ar-H), 7.77 (2H, m, Ar-H); m/e (FAB+), 408 (M+1), 93 (100%); Found C, 49.05; H, 4.43; N, 8.94; C19H19Cl2N3O3. 1.5HCl requires C, 49.29; H, 4.46; N, 9.08%.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][CH3:13])[CH2:4][NH:5][C:6](=[O:11])[C:7]([O:9]C)=O.[Cl:14][C:15]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>C(Cl)Cl.Cl>[Cl:14][C:15]1[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:2]1[C@@H:3]([CH2:12][CH3:13])[CH2:4][NH:5][C:6](=[O:11])[C:7]1=[O:9]
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: CC[C@H](N)CNC(=O)C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1CNC(=O)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 37.7 %

Procedure:
To an ice cold solution of (S)-methyl 2-((2-aminobutyl)amino)-2-oxoacetate hydrochloride (967 mg, 4.6 mmol) and 2-chloro-3-trifluoromethylbenzaldehyde (957 mg, 4.6 mmol) in DCM (26 mL) was added sodium triacetoxyborohydride (1.46 g, 6.9 mmol). The resulting mixture was allowed to warm to rt and stirred for 13 h. Triethylamine (1.9 mL) was added, and after 2 h the reaction was diluted with 1M HCl. The organic layer was washed with sat. aq. NaHCO3 and brine, then dried (Na2SO4), and concentrated to afford a clear oil. Purification by chromatography (SiO2; hexanes—10% IPA/EtOAc) provided the desired product as a white solid (580 mg, 38%). MS (ESI): mass calcd. for C14H14ClF3N2O2, 334.1; m/z found, 335.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J=4.5 Hz, 1H), 7.68 (dd, J=7.8, 1.1 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 5.28 (d, J=15.5 Hz, 1H), 4.48 (d, J=15.5 Hz, 1H), 3.70 (dd, J=13.4, 4.2 Hz, 1H), 3.44 (ddd, J=13.4, 5.5, 1.6 Hz, 1H), 3.37-3.28 (m, 1H), 1.25-1.17 (m, 2H), 0.99 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.Cl[CH2:19][CH:20]=O>O.C(O)(C)C>[N:1]1[CH:19]=[CH:20][N:7]2[C:2]=1[CH:3]=[C:4]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[N:6]2
Reactant: COC(=O)c1cccc(-c2cnnc(N)c2)c1
Reactant: O=CCCl
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1cccc(-c2cnn3ccnc3c2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 3-(6-aminopyridazin-4-yl)benzoate (0.20 g, 0.87 mmol) and chloroacetaldehyde in water (0.3 mL, 50%) in isopropyl alcohol (3.0 mL) was stirred at 100° C. for 4 h. The solvent was removed and the residue was dissolved in ethyl acetate, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in methylene chloride (0-30%) to afford the desired product (0.18 g). LCMS (M+H)+: m/z=254.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.[CH3:25][C:26]1([CH3:40])[C:30]([CH3:32])([CH3:31])[O:29][B:28]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[O:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:37][C:36]2[CH:38]=[CH:39][C:33]([B:28]3[O:27][C:26]([CH3:40])([CH3:25])[C:30]([CH3:31])([CH3:32])[O:29]3)=[CH:34][CH:35]=2)[CH:18]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CNc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Yield: 88.6 %

Procedure:
2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-carbaldehyde (1.0 g) synthesized according to a method described in [WO 2008/001931 pamphlet, (Reference Example 18)] and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.63 g) were dissolved in methylene chloride (10 mL), and to the resultant solution, sodium triacetoxyborohydride (1.84 g) was added, followed by stirring the resultant reaction mixture at room temperature for 14 hours. To the reaction mixture, water (20 mL) was added, followed by extracting the reaction mixture with methylene chloride (20 mL) twice, and the resultant organic phase was washed sequentially with water (50 mL) and a saturated saline (50 mL) and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure to obtain the subject compound (1.4 g) as a colorless amorphous solid.