Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[N+:16]([O-])([OH:18])=[O:17]>C(OC)(C)(C)C>[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:8]=1[CH:9]=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)C
Product: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 42 °C
Reaction time: 1.83 h
Yield: 28.7 %

Procedure:
Concentrated sulphuric acid (450 Kg) was added to 2,3-dichlorobenzaldehyde (59 Kg) and the mixture was heated to 40-44° C. for 2 hours, with stirring, to dissolve all the solids then cooled to 20-25° C. over a period of 95 minutes. Nitric acid (70% w/w, 34.5 Kg) was added to the solution, maintaining the temperature between 16 and 28° C., over a period of 110 minutes. The reaction mixture was stirred for 130 minutes, at between 21-25° C., and then quenched by controlled addition over 225 minutes into 1080 Kg of water (pre-cooled to 0-5° C.), maintaining the temperature between 2-20° C., including a vessel rinse of concentrated sulphuric acid (9.2 Kg). The resulting suspension was stirred for 180 minutes at between 10-14° C. then isolated by filtration and washed with pre-cooled (0-15° C.) water (2×297 Kg). The isolated crude solid (151.3 Kg crude, 51.6 kg active weight) was dissolved in methyl tert-butyl ether (590 L) and washed with water (165 L), 10% w/w sodium carbonate solution (165 L) and then water (1654 Solvent was removed by reduced pressure distillation at 17-20° C. until a volume of 160 L was reached, whereupon heptane (1140 L) was added. The resulting slurry was heated to 60° C. over 54 minutes and stirred at between 60-65° C. for 110 minutes, then cooled to 15-20° C. over 11.5 hours. Material was isolated by filtration and washed with heptane 90 L) then dried in vacuo at 40-45° C. to give 2,3-dichloro-6-nitrobenzaldehyde (21.3 Kg) with 96.3% purity (HPLC) in 29% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:17])[C:9]([C:14]([OH:16])=O)=[CH:10][NH:11]2)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:17])[C:9]([C:14]([NH:30][C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[O:16])=[CH:10][NH:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(=O)c(C(=O)O)c[nH]c2n1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCOc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)c[nH]c2n1

Procedure:
7-Ethoxy-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.9 g) and N,N-carbonyldiimidazole (2 g) in dimethylformamide (50 ml) were stirred and heated at 100° for 4 hours. 5-Amino-1H-tetrazole (2.1 g) was added and the mixture stirred and heated at 100° for 30 minutes, and cooled. The solid was collected and dissolved in hot (60°) dilute sodium hydroxide and the solution was neutralised (pH 7) with dilulte hydrochloric acid. The solid was collected, washed with water and dried, m.p. above 319° (d), (75 %).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[C:32]([O:31][C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:13]1[CH:14]=[C:15]([CH3:16])[C:7]2[CH:6]([CH2:5][C:4]([OH:36])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(OCCCNC(=O)OC(C)(C)C)c3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2cccc(OCCCNC(=O)OC(C)(C)C)c2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C

Procedure:
To a solution of {6-[3-(3-tert-butoxycarbonylamino-propoxy)-phenoxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.6 g, 1.2 mmol) in THF:H2O (1:1, 10 mL) at 0° C. was added a solution of LiOH (0.086 g, 3.6 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 3 hours then acidified to pH 2 with 1N HCl at 0° C. and extracted with EtOAc (2×10 mL). The organic extracts were dried and concentrated in vacuo to give crude 6-[3-(3-tert-butoxycarbonylamino-propoxy)-phenoxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.5 g) which was used without further purification MS (ESI) m/z=470 [M−H]−.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(N(CC)CC)C>ClCCl>[CH2:14]([O:13][C:11]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyl 3-aminopropionate hydrochloride (2.00 g, 13.0 mmol) was dissolved in dichloromethane (40 ml), and benzyl chloroformate (2.00 ml, 14.1 mmol) was added. With cooling with ice, triethylamine (4.00 ml, 28.9 mmol) was added, followed by stirring at room temperature for 15 hours, then the reaction, liquid was concentrated. Ethyl acetate and water were added, the organic layer was collected, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a pale yellow oil (3.26 g, quant).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([Cl:19])=[O:15])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(C(=O)O)c2ccccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(C(=O)Cl)c2ccccc2c1
Yield: 100 %

Procedure:
3-Cyano-1-naphthoic acid (see Bioorg. Med. Chem. Lett. 2001, 2769; 1.1 g, 5.6 mmol) was slurried in CH2Cl2 (10 mL) and then oxalyl chloride was added with stirring. A drop of DMF was added and the mixture stirred at room temperature overnight under nitrogen. The solvent was removed by evaporation and there was obtained 1.2 g (100%) of 3-cyano-1-naphthoyl chloride as a pale yellow solid. 1H NMR (300 MHz, CDCl3): 7.7-7.8 (m, 1H), 7.8-7.9 (m, 1H), 8.0-8.1 (m, 1H), 8.5 (s, 1H), 8.7 (s, 1H), 8.8 (d, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=O.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH:26]([NH:29][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:2])([CH3:28])[CH3:27]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Reactant: CC(C)N
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC(C)C)n(C)n1
Yield: 88 %

Procedure:
As described for example 48c, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using isopropylamine instead of N,N-dimethylhydrazine, to the title compound (95 mg, 88%) which was obtained as a colorless oil. MS: m/e=373.1 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)cc4F)c3O2)cc1
Product: CNCC1Cc2cccc(-c3ccc(F)cc3F)c2O1

Procedure:
The title compound was prepared (0.137 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.366 g, 0.88 mmol) and methylamine (0.273 g, 8.80 mmol). mp 156-160° C.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.C(OC(=O)C)C>CCCCCC>[C:4]1(=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5]1
Reactant: CCOC(=O)NCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1NCCc2ccccc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 1.3 %

Procedure:
Phenethyl-carbamic acid ethyl ester (I-23a: 9 g, 46.875 mmol) and poly phosphoric acid (187.5 g) were taken in a flask and the flask was heated to 120° C. for 4 hours. The reaction was monitored by TLC (30% ethylacetate in hexane). The reaction mixture was partitioned between chilled water and ethylacetate. The resulting mixture was stirred at 115° C. for 2 hours to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 0.090 g of the product (9.1% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:15](#[N:19])[CH:16]([CH3:18])[CH3:17]>>[O:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:15](=[NH:19])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:11]1
Reactant: CC(C)C#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: Cl
Product: CC(C)C(=N)Nc1ccccc1N1CCOCC1
Temperature: 165 °C

Procedure:
A mixture of 4-(2-aminophenyl)morpholine hydrochloride (10 g) and isobutyronitrile (60 ml) was heated at 165° C. for 26 hours in a sealed stainless steel pressure vessel to yield N-(2-morpholinophenyl)isobutyramidine (m.p. 140°-141° C.) which was recrystallised from hexane.
Reaction SMILES: [C:1]1([PH:7](=[S:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].[OH-].[K+].O>C(Cl)Cl>[C:19]1([C:17]([CH2:16][P:7](=[S:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: S=[PH](c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(CP(=S)(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
A stirred mixture of diphenylphosphine sulfide (0.218 g, 0.001 mol) and chloroacetophenone (0.216 g, 0.0014 mol) in methylene chloride (4 ml) was cooled to 8–10° C. in an ice-water bath. Small pieces of solid potassium hydroxide (0.196 g, 0.0035 mol) were added while stirring under nitrogen atmosphere. After 45 minute, water (2 ml) was added and the organic layer was separated, washed with more water (2 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure using a rotary evaporator and the oily residue was crystallized from ethyl acetate-hexane mixture to give 0.19 g (56.5%) of star shaped crystals. mp=83–84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(c1ccc(Cl)cc1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(c1ccc(Cl)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
4.63 g (18.3 mmol) of methyl (4-chlorophenyl)(cyclopentyl)acetate were dissolved in a mixture of 18.5 ml of THF and 18.5 ml of methanol, and 73.3 ml of 10% strength aqueous sodium hydroxide solution (183.2 mmol) were added at RT. The reaction mixture was stirred at RT overnight. The mixture was then acidified by addition of 1 N hydrochloric acid. The aqueous phase was repeatedly extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. This gave 4.31 g of the target compound as a crude product (yield 98.6% of theory).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-])=[CH:11][C:10]=2[N:9]=[C:8]1[CH3:21])(=[O:3])[CH3:2].CN(C)C=O.P(Cl)(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([Cl:29])[C:10]=2[N:9]=[C:8]1[CH3:21])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OCCn1c(C)nc2c[n+]([O-])c3ccccc3c21
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OCCn1c(C)nc2c(Cl)nc3ccccc3c21
Reaction time: 0.5 h

Procedure:
A dried round bottom flask was charged with a stir bar, 2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (8.7 g, 30.49 mmol), anhydrous dimethylformamide (80 mL), and anhydrous toluene (100 mL) under nitrogen. To this brown mixture was added phosphorus oxychloride (3.1 mL) by syringe at ambient temperature. The reaction solution cleared in a couple of minutes and a slight exotherm was observed. The reaction was judged to be complete after 30 minutes. The volatiles were removed under reduced pressure. The resulting brown solid was partitioned between dichloromethane and 4% aqueous sodium bicarbonate to a pH of 8. The aqueous layer was extracted with dichloromethane (5×). The organic fractions were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure and dried overnight at ambient temperature under reduced pressure to provide 9.2 g of 2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH:6]=[CH:5]2.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.C(OCC)(=O)C>[CH3:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[CH:3]=2)[N:8]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3ccc(C#N)cc3)ccc2n1
Temperature: 25 °C

Procedure:
The product from Example 42D (160 mg, 0.5 mmol), 4-cyanophenylboronic acid (0.75 mmol), and dichlorobis(triphenylphosphine) palladium (II) (35.1 mg, 0.05 mmol) were combined in isopropyl alcohol (5.0 mL) and 0.2 M K3PO4 aq. solution (5.0 mL, 1.0 mmol) and heated at 60° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (20 mL). The organic phase was separated, washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with one equivalent of L-tartaric acid in IPA:ethanol to give the tartrate salt. mp 164° C.; MS (ESI) 342 (M+H)+; 1H NMR (DMSO-d6) δ 8.40 (1H, d), 8.38 (1H, d), 8.12 (1H, d), 8.06 (1H, d), 8.04 (2H, d), 7.98 (2H, d), 7.58 (1H, d), 4.05 (2H, s), 3.63 (1H, m), 3.50 (1H, m), 3.33 (2H, t), 3.15 (2H, m), 2.88 (1H, m), 2.09 (1H, m), 1.86 (2H, m), 1.55 (1H, m), 1.29 (3H, d).
Reaction SMILES: [NH3:1].[CH3:2][C:3]1O[CH:8]=[CH:7][C:5](=[O:6])[C:4]=1[OH:10]>>[CH3:2][C:3]1[CH:4]([OH:10])[C:5](=[O:6])[CH:7]=[CH:8][N:1]=1
Reactant: Cc1occc(=O)c1O
Reactant: N
Product: CC1=NC=CC(=O)C1O

Procedure:
An ammonia solution is added to a solution of maltol dissolved in hot distilled water. The pH of this solution is adjusted to 9.8 by the addition of HCl solution. The mixture is kept under reflux overnight and then decolorized with activated charcoal. The solvent is removed under reduced pressure. The white product is obtained upon recrystallization from hot water.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]3[C:10]=2[C:5]([C:6](=[O:19])[CH2:7][CH2:8]3)=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>C(O)C>[OH:19][CH:6]1[C:5]2[C:10]3=[C:11]([CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]3[CH2:8][CH2:7]1)[C:2]([CH3:1])=[CH:3][CH:4]=2
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Ethyl 5,6-dihydro-9-methyl-6-oxo-4H-pyrrolo [3,2,1-ij]quinoline-2-carboxylate (3.00 g, 11.7 mmol) was added to a mixture of tetrahydrofuran (20 ml) and ethanol (80 ml), and the reaction mixture was cooled to 0° C. Then, sodium borohydride (0.44 g, 11.7 mmol) was added and the resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and then a 5% aqueous sodium hydroxide solution were added to the residue. After being separated, the aqueous layer was further extracted twice with ethyl acetate, and the combined organic layer was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 1/9) to obtain 2.40 g of ethyl 5,6-dihydro-6-hydroxy-9-methyl-4H-pyrrolo [3,2,1-ij]-quinoline-2-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]>C(N(CC)CC)C>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][S:36]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Nc1ccc(C(=O)Nc2ccc(OC)cc2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 20 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide (500 mg, 1.20 mmol) was reacted with butylsulfonyl chloride in the presence of triethylamine to yield 130 mg (20%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](S(C)=O)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH3:40])[N:25]=2)[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:9][C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH3:40])[N:25]=2)[CH2:21][CH2:22]1
Reactant: CNc1ncc(-c2ccnc(S(C)=O)n2)c(CC2CC2)n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1ncc(-c2ccnc(Nc3ccc(OC)nc3)n2)c(CC2CC2)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
To a solution of 6-methoxypyridin-3-amine (61.4 mg, 0.494 mmol) in THF (5 mL) cooled to −78° C., lithium bis(trimethylsilyl)amide (1M in THF, 0.494 mL, 0.494 mmol) was added dropwise under nitrogen. After the reaction was stirred at −78° C. for 10 minutes, a solution of 4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-1) (30 mg, 0.099 mmol) in THF (1 mL) was added to the reaction at −78° C. The reaction was slowly warmed up to rt, then the reaction was allowed to stir for 1 hour. The reaction was quenched with saturated ammonium chloride solution, then concentrated in vacuo. The reaction was taken up in acetonitrile, purified by reverse-phase HPLC [10-90% organic phase over 15 minutes], then further purified by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 7% MeOH/DCM] to afford the title compound as a white solid (19.49 mg, 46.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.04 (br. s., 2 H) 0.34 (d, J=7.58 Hz, 2 H) 1.01 (br. s., 1 H) 2.77 (d, J=6.57 Hz, 2 H) 2.86 (d, J=4.55 Hz, 3 H) 3.74-3.86 (m, 3 H) 6.78 (d, J=9.09 Hz, 1 H) 6.97 (d, J=5.05 Hz, 1 H) 7.36 (d, J=4.04 Hz, 1 H) 7.99 (dd, J=8.59, 2.53 Hz, 1 H) 8.35-8.50 (m, 3 H) 9.46 (s, 1 H). HRMS (ES+) for C19 H21N7O.H+ [MH+]: calcd, 364.1886. found, 364.1891. UV-LC: 94.60/100% UV purity at 254/214 nm; tR=5.08 minutes over 7.75 minutes.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:9]1[C:10](=[O:20])[C:11]2[C:12](=[CH:13][C:14]([F:18])=[C:15]([F:17])[CH:16]=2)[NH:19][C:29]1=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)NN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 198.7 %

Procedure:
2-Amino-4,5-difluorobenzoic acid, 2,2-dibenzylhydrazide (Example 15) (0.81 g, 2.2 mmol) and triphosgene (0.33 g, 1.1 mmol) are combined in 100 mL of methylene chloride and stirred at 25° C. for 20 hours. The solution is poured into 200 mL of saturated NaHCO3, the layers are separated, and the aqueous layer is washed three times with ethyl acetate. The combined organic layers are dried over magnesium sulfate and then concentrated to give 0.86 g of the title compound as a solid. MS CI: m/z 394 (MH+).
Reaction SMILES: [CH3:1][S:2]([O:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)(=[O:4])=[O:3].Br[C:20]1C=CC(O[C@@H]2CCCC[C@H]2O)=CC=1>>[CH3:1][S:2]([O:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][CH2:20][C@H:7]1[O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1
Reactant: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Product: CS(=O)(=O)O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1

Procedure:
The title compound of Step 4 was prepared according to the general procedure for the synthesis of trans-2-(4-bromophenoxy)cyclopentyl methanesulfonate in Example 5, except that (1R,2R)-2-(4-bromophenoxy)cyclohexanol was used instead of trans-2-(4-bromophenoxy)cyclopentanol. (1R,2R)-2-(4-bromophenoxy)cyclohexyl methanesulfonate was obtained as a light golden oil. Yield: 3.60 g, 10.3 mmol, quantitative. 1H NMR (400 MHz, CDCl3) δ 1.26-1.51 (m, 3H), 1.64-1.84 (m, 3H), 2.19 (m, 1H), 2.30 (m, 1H), 2.97 (s, 3H), 4.22 (ddd, J=10.2, 8.5, 4.6 Hz, 1H), 4.64 (ddd, J=10.6, 8.4, 4.9 Hz, 1H), 6.82 (d, J=9.1 Hz, 2H), 7.39 (d, J=9.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C=O)=[N:4][C:3]=1[CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.O1CCCC1.Cl>C(O)C>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=1
Reactant: O=CNc1nc(CSc2ccncc2)c(Cl)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1nc(CSc2ccncc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.9 %

Procedure:
A solution of 5-chloro-2-formylamino-4-(4-pyridylthiomethyl)thiazole (4.9 g) in a mixture of ethanol (25 ml), tetrahydrofuran (20 ml) and concentrated hydrochloric acid (7 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8 using aqueous sodium bicarbonate under ice-cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-chloro-4-(4-pyridylthiomethyl)thiazole (0.26 g, yield: 56.6%).