Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>C(Cl)Cl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([S:10]([Cl:9])(=[O:12])=[O:11])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
108 grams of anisole (1.0 mol) was added to 700 ml of CH2Cl2 in a one-liter round bottom flask and cooled to 0°-5° C. While using ice-bath cooling to maintain the temperature below 10° C., 280 grams of chlorosulfonic acid (1.5 mol) was added dropwise with magnetic stirring over a 4 hour period. The solution was then carefully poured over ice (1500 grams) and the organic layer collected. The solution was washed in the cold 10% NaHCO3, and the organic layer collected, then dried over MgSO4 and filtered. The solvent was removed in a rotary evaporator under aspirator vacuum and crude 4-methoxy- benzenesulfonylchloride (72% yield) was obtained as a red oil in a sufficient state of purity to permit its use without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:8]([NH:10][C@@H:11]2[C:31](=[O:32])[N:13]3[C:14]([C:28]([O-:30])=[O:29])=[C:15]([CH2:18][N+:19]4[N:23]5[CH2:24][CH2:25][CH2:26][NH:27][C:22]5=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[C:8]([NH:10][C@@H:11]2[C:31](=[O:32])[N:13]3[C:14]([C:28]([O-:30])=[O:29])=[C:15]([CH2:18][N+:19]4[N:23]5[CH2:24][CH2:25][CH2:26][NH:27][C:22]5=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4n3CCCN4)CS[C@H]12)c1csc(N)n1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(C(=NOCC(=O)O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccc5n4CCCN5)CS[C@H]23)cs1
Reaction time: 3 h
Yield: 41.2 %

Procedure:
To a suspension of 7β-[2-(2-aminothiazol-4-yl}-2-t-butoxycarbonylmethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate (syn isomer) (800 mg) in methylene chloride (2.4 ml) and anisole (0.8 ml) was added dropwise trifluoroacetic acid (1.6 ml) at 20° C. The stirring was continued for 3 hours at the room temperature. The reaction mixture was poured into ethyl acetate. The resulting precipitates were collected by filtration. The precipitates were dissolved in water (50 ml) and the mixture was adjusted to pH 6.5 with a saturated aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on HP-20 using water as an eluent and the object fractions were adjusted to pH 2.0 with 1N hydrochloric acid. The resulting solution was subjected to column chromatography on HP-20 using 15% aqueous isopropyl alcohol as an eluent and the object fractions were lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido] -3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate (syn isomer) (300 mg).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:21][CH:22]=2)=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(Br)cc2)CC1
Product: Brc1ccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-bromophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-bromophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c2c1OCO2
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)O)c2c1OCO2
Yield: 98.7 %

Procedure:
8.05 g of 7-nitro-benzo[1,3]dioxole-4-carboxylic acid is reacted with hydrogen in 650 ml of ethanol with 800 mg of palladium/carbon catalyst under normal pressure at room temperature. It is filtered through diatomaceous earth and concentrated by evaporation in a vacuum. 6.82 g of 7-amino-benzo[1,3]dioxole-4-carboxylic acid is obtained as a brown solid, flash point 196–197° C.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]3[CH:12]=[C:13]([C:16]([NH2:18])=O)[CH:14]=[CH:15][C:6]3=[N:5][C:4]=2[CH:3]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]3[CH:12]=[C:13]([C:16]#[N:18])[CH:14]=[CH:15][C:6]3=[N:5][C:4]=2[CH:3]=1
Reactant: Cc1cc2nc3ccc(C(N)=O)cn3c(=O)c2s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cc2nc3ccc(C#N)cn3c(=O)c2s1

Procedure:
2-Methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide (Example 44), 0.6 g (0.0023 mol), in 10 of pyridine, 25 ml of phosphorous oxychloride and 25 ml of chloroform is refluxed on a steam bath for three hours. The solvents are evaporated in vacuo and the residue is treated with 100 ml of ice water. The resulting precipitate is filtered to give 0.5 g of 2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitrile; mp 258°-259° C. after recrystallization from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: Nc1cccc(N)n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Nc1cccc(Nc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
2,6-Diaminopyridine (9.2 mmol, 1.0 g) and 1-fluoro-4-nitrobenzene (9.2 mmol, 1.3 g) were dissolved in 10 mL anhydrous DMF. The solution was stirred at ambient temperature while 95% sodium hydride (18.3 mmol, 440 mg) was added. The solution turned reddish black in 30 min. The reaction mixture was stirred for an additional 20 hours at room temperature. The reaction mixture was poured slowly into 25 mL 10% aqueous NH4Cl solution mixed with ice (25 g). The resulted aqueous solution was extracted with EtOAc (4×30 mL). The combined organic phase was dried over MgSO4 and evaporated to dryness. The residual oil was purified by flash column chromatography on silica gel (EtOAc:Hexane 1:2) to provide N2-(4-nitrophenyl)pyridine-2,6-diamine (1.6 g, 76%), a reddish orange crystal: 1H NMR (500 MHz, CDCl3) δ 8.19 (d, 2H, J=9.0 Hz), 7.51 (d, 2H, J=9.0 Hz), 7.42 (t, 1H, J=8.0 Hz), 6.85 (s, 1H), 6.30 (d, 1H, J=8.0 Hz), 6.16 (d, 1H, J=8.0 Hz), 4.51 (s, 2H); MS m/z (relative intensity) 231 (M+1, 100), 184 (100). N2-(4-nitrophenyl)pyridine-2,6-diamine (2.6 mmol, 0.6 g) and 10% Pd/C (30 mg) were added to a 20 mL test tube equipped with a stir bar and then dry ice (0.5 g, CO2) was added to the mixture just before MeOH (8 mL) was added. The suspension was then put into a pressure vessel under 80 psi H2. The reaction mixture was stirred for 3 hours. The solution turned from yellow to colorless. The reaction mixture was transferred into a 10 mL syringe and filtered through an Acrodisc syringe Filter into a 100 mL round bottom flask containing 37% aqueous HCl (4 mL). The solvent was then evaporated and azeotroped to dryness with toluene and absolute ethanol (3×30 mL of 1:1 mixture). The product was obtained as an off-white powder in quantitative yield: 1H NMR (500 MHz, D2O) δ 7.48 (t, 1H, J=14.0 Hz), 7.25 (m, 4H), 6.13 (d, 1H, J=14.0 Hz), 6.09 (d, 1H, J=14.0 Hz); Ms m/z (relative intensity) 201 (M+1, 100).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with aminodiphenylmethane (42 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 66 mg of the title compound as a colorless solid.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[CH:24]=[N:25][C:26]([C:27](O)=[O:28])=[C:22]3[C@@H:21]3[CH2:30][CH2:31][CH2:32][N:20]3[C:19](=[O:33])[C:18]=2[C:34]=1[F:35].N>CN(C)C=O>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[CH:24]=[N:25][C:26]([C:27]([NH2:3])=[O:28])=[C:22]3[C@@H:21]3[CH2:30][CH2:31][CH2:32][N:20]3[C:19](=[O:33])[C:18]=2[C:34]=1[F:35]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1F
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
6.1 g (37.9 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 11 g (34.5 mmol) of (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid in 80 ml of dimethylformamide. The resulting pale brown solution was heated to 50° for 45 minutes. The solution was subsequently cooled to room temperature and 12 ml of aqueous ammonia solution were added dropwise. After stirring for a further 30 minutes the reaction mixture was poured into 150 ml of ice-water and extracted seven times with methylene chloride. Drying of the organic phases with sodium sulfate, filtration and evaporation yielded a colourless residue which was triturated with methylene chloride. After drying in a high vacuum there were obtained 9.8 g of (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide m.p. 221°-224°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cnc(Cl)nc1Cl
Yield: 80 %

Procedure:
A heterogeneous solution of 2.4-dichloro-5-nitro-pyrimidine (1.0 eq.) and iron (6.0 eq) in acetic acid, at a concentration of 0.4 M, was stirred vigorously for 14 hours. The mixture was then passed through a celite pad, eluting with MeOH. Upon removal of the volatiles in vacuo, the residue was dissolved in EtOAc, washed with Na2CO3(sat.), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding 2,4-dichloropyrimidin-5-amine (80%). LCMS (m/z): 157.0 (MH+); LC Rt=1.85 min.
Reaction SMILES: Cl[C:2]1[N:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[N:9]([N:10]=[C:11]([CH3:13])[CH:12]=3)[C:4]=2[CH:3]=1.CN(C)C=O.[H][H]>[Pd].C(N(CC)CC)C>[CH3:13][C:11]1[CH:12]=[C:8]2[NH:7][C:6](=[O:14])[C:5]3[CH:15]=[N:16][CH:2]=[CH:3][C:4]=3[N:9]2[N:10]=1
Reactant: [H][H]
Reactant: Cc1cc2[nH]c(=O)c3cnc(Cl)cc3n2n1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc2[nH]c(=O)c3cnccc3n2n1

Procedure:
2.3 g. of 8-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one are hydrogenated in 50 ml. of dimethylformamide in the presence of 10% palladium on charcoal and 2 g. of triethylamine at 80° and 3 atmospheres hydrogen pressure. When the hydrogen absorption ceases, the solution is heated to reflux temperature and then filtered. After addition of 20 ml. of water, 2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one crystallizes, yield: 1.8 g. (90%); m.p. > 300°.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[S:19]1[CH:23]=[CH:22][N:21]2[CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=[C:20]12.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:25]3[N:26]=[C:20]4[N:21]([CH:24]=3)[CH:22]=[CH:23][S:19]4)=[O:28])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2ccsc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2ccsc2n1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.31 g, 1.19 mmol), imidazo[2,1-b]thiazole-6-carboxylic acid (0.2 g, 1.19 mmol), HOBt (0.24 g, 1.78 mmol), DIPEA (0.62 mL, 3.57 mmol) and EDCI (0.34 g, 1.78 mmol) using DMF (10 mL) as solvent using the method of Example 34(d) affording 232 mg of the product. 1H NMR (400 MHz; MeOD): δ 1.24 (d, 3H), 4.38 (m, 2H), 4.55 (m, 1H), 6.76 (d, 1H), 7.21 (d, 1H), 7.75 (m, 3H), 7.90 (dd, 1H), 8.06 (m, 1H), 8.09 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:33])=[C:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:6]=1[C:7]([NH:9][C:10]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+:35]>CCO>[CH3:1][C:2]1[S:3][C:4]([CH3:33])=[C:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=2)[C:6]=1[C:7]([NH:9][C:10]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([O-:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[Na+:35]
Reactant: Cc1sc(C)c(C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(C)c(C(=O)NC2(c3ccc(C(=O)[O-])cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
A solution of 4-{1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]cyclopropyl}benzoic acid from Example 16, Step 4 (112 mg, 0.236 mmol) in EtOH (5 mL), was treated with NaOH (1.0N in water, 236 μL, 0.236 mmol) after which a precipitate was formed. The mixture then obtained was concentrated to dryness. Water (15 mL) was added to the residue. The very fine resulting suspension was frozen in a bath of dry ice and acetone and lyophilized to afford the desired product as a white fluffy solid. MS (−APCI): m/z 472 (M−23)−.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](O)=[O:10]>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:10]
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Product: O=C(NC1CC1)c1ccc(F)c(Cl)c1
Yield: 89 %

Procedure:
Using cyclopropylamine and 3-chloro-4-fluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (89% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.56 (d, J=3.5 Hz, 1H), 8.03 (dd, J=7.3, 2.3 Hz, 1H), 7.85 (ddd, J=8.6, 4.8, 2.3 Hz, 1H), 7.52 (t, J=9.0 Hz, 1H), 2.83 (tq, J=7.4, 3.9 Hz, 1H), 0.66-0.75 (m, 2H), 0.53-0.61 ppm (m, 2H). ESI-MS: m/z 214.0 (M+H)1.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCOCC1
Temperature: 60 °C
Yield: 32.9 %

Procedure:
In the manner described in Example 21C, 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.38 mmol) from Example 21B was reacted with morpholine (99 μL, 1.14 mmol), diisopropylethyl amine (199 μL, 1.14 mmol), and tetrabutyl ammonium iodide (140 mg, 0.38 mmol). After heating at 60° C. overnight the reaction was cooled to room temperature, and 10 mL of water added. The resulting precipitate was collected by filtration and purified by HPLC on a phenyl-hexyl reverse phase column eluting with an acetonitrile/water gradient 35-55% over 60 minutes. The major peak was collected, neutralized to pH-8 with saturated sodium bicarbonate and extracted twice with ethyl acetate. The extracts were combined, dried with magnesium sulfate, and concentrated to a solid. The solid was triturated with 20:1 methanol water and the solid removed by filtration and dried to give 72 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.99 (s, 1H), 8.55 (s, 1H), 7.58 (m, 2H), 7.39 (m, 2H), 7.26 (m, 1H), 6.99 (m, 1H), 6.47 (s, 1H), 4.25 (m, 2H), 3.99 (s, 3H), 3.58 (m, 4H), 2.5-2.35 (m, 6H), 1.97 (m, 2H), 1.30 (s, 9H). LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:6][CH:7]=1.[CH:26]1([C:29]([CH3:31])=O)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:29]([CH:26]3[CH2:28][CH2:27]3)[CH3:31])[CH2:21][CH2:20]2)=[N:6][CH:7]=1
Reactant: CC(=O)C1CC1
Reactant: Cc1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(NCC2CCN(C(C)C3CC3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]-5-methylbenzamide from Example 204 (1.0 g, 2.78 mmol) in 6 mL of 95:5 methanol-acetic acid was treated with excess cyclopropylmethyl ketone (5.52 mL, 55.6 mmol), followed by sodium cyanoborohydride (0.65 g, 10.3 mmol). After stirring at room temperature for 24 hr, the reaction mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol afforded 0.76 g (64%) of the title compound as a yellow solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[Br:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32](Br)[C:31]([F:38])=[CH:30][N:29]=1>CN1C(=O)CCC1.CCOC(C)=O>[Br:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32]([N:15]2[CH2:16][CH2:17][CH:12]([C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[O:11])[CH2:13][CH2:14]2)[C:31]([F:38])=[CH:30][N:29]=1
Reactant: CN1CCN(C(=O)C2CCNCC2)CC1
Reactant: O=[N+]([O-])c1c(Br)ncc(F)c1Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN1CCN(C(=O)C2CCN(c3c(F)cnc(Br)c3[N+](=O)[O-])CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A round-bottomed flask was charged with (4-methylpiperazin-1-yl)-(4-piperidyl)methanone dihydrochloride (16.45 g, 57.89 mmol) and DIPEA (23.20 g, 31.27 mL, 179.5 mmol) in NMP (160 mL). 2,4-Dibromo-5-fluoro-3-nitro-pyridine (17.36 g, 57.89 mmol) was added and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. Additional (4-methylpiperazin-1-yl)-(4-piperidyl)methanone dihydrochloride (1.65 g, 0.1 eq) and DIPEA (1 mL, 0.1 eq) was added and stirred at room temperature for a further 3 h. The mixture diluted with EtOAc, washed with water (3×). The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were combined, washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography (330 g SiO2, 0 to 5% MeOH (containing 10% ammonium hydroxide)/DCM) to afford product as a yellow solid (20.24 g, 81%). MS (ES+) 432.0.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].F[C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][C:29]=1[C:39]([N:41]1[CH2:50][CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40]>>[Cl:13][C:12]1[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:23][CH2:24][CH2:25][CH3:26])=[N:9][N:10]([C:28]2[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][C:29]=2[C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[C:11]=1[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(CCOC2CCCCO2)c1Cl
Reactant: CCOC(=O)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)c(CCOC2CCCCO2)c1Cl
Yield: 29.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, N,N-dibutyl-4-chloro-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole-3-carboxamide (407 mg, 1.06 mmol) and ethyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (380 mg, 1.16 mmol) were converted to the title compound (219 mg, 30%). 1H NMR (CD3OD, mixture of amide rotamers) δ 8.26 (td, J=8.4, 1.8 Hz, 1H), 8.19-8.10 (m, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.29-7.07 (m, 3.5H), 6.94 (d, J=7.5 Hz, 0.5H), 4.71-4.48 (m, 2H), 4.47-4.39 (m, 2H), 4.16-3.86 (m, 1H), 3.80-3.37 (m, 5H), 3.26-2.58 (m, 5H), 1.87-0.74 (m, 22H), 0.72-0.66 (m, 1H); MS(ESI+) m/z 609.3 (M+H-THP)+.