Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)C(C)C)(C)C.[Br:23][C:24]1[CH:28]=[N:27][N:26]([CH3:29])[C:25]=1[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]([CH3:44])([N+:41]([O-])=O)[CH3:40])[NH2:33].C(O)(=O)C.[OH-].[NH4+]>ClCCl.[Zn]>[NH2:41][C:39]([CH3:44])([CH3:40])[CH2:38][O:37][C:36]1[CH:35]=[CH:34][C:32]([NH:33][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[CH:31][C:30]=1[C:25]1[N:26]([CH3:29])[N:27]=[CH:28][C:24]=1[Br:23]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)N
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 3-trifluoromethylbenzoyl chloride (17 μl, 0.11 mmol), N,N-diisopropylethylamine (21 μl, 0.12 mmol) and 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (37 mg, 0.10 mmol) in 0.5 mL of dichloromethane was stirred at room temperature. After 1 h the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was taken up in methanol (0.4 mL), acetic acid (114 μl, 2.0 mmol) was added followed by zinc dust (65 mg, 1.0 mmol) and the mixture was stirred at room temperature. After 1 h the mixture was made strongly basic with conc ammonium hydroxide, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative LCMS and lyophilized to afford the product (46 mg, 74%) as a TFA-salt. LCMS m/z (%)=513.5 (M+H 81Br 71.7%), 511.3 (M+H 79Br 82.9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 3H), 1.18 (s, 3H), 3.67 (s, 3H), 3.84 (d, J=9.60 Hz, 1H), 4.00 (d, J=9.85 Hz, 1H), 7.31 (d, J=9.09 Hz, 1H), 7.67 (s, 1H), 7.70 (d, J=2.78 Hz, 1H), 7.80 (t, J=7.71 Hz, 1H), 7.86-7.94 (m, 3H), 7.94-8.01 (m, 2H), 8.26 (d, J=8.08 Hz, 1H), 8.29 (s, 1H), 10.57 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9].[NH2:16][C:17]1[C:18]([C:39]#[N:40])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]=2[F:38])=[CH:21][N:22]=1>>[NH2:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:2]3[C:3]([S:8]([NH:11][C@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:25][C:24]=2[F:38])=[N:19][C:18]=1[C:39]#[N:40]
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Reactant: C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Product: C[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)c(C#N)n2)c(F)c1

Procedure:
The title compound was prepared in manner similar to that described in Example 88 using (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C20H18FN5O3S, 427.11; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J=2.1, 1H), 8.16 (dd, J=7.9, 1.4, 1H), 7.93 (m, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.45-7.28 (m, 3H), 3.47-3.36 (m, 1H), 3.34-3.18 (m, 2H), 1.03 (d, J=6.6, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:19])([CH2:14][O:15][CH2:16][O:17][CH3:18])[CH2:9][O:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:19][C:28](=[O:29])[CH2:27][Cl:26])([CH2:9][O:10][CH2:11][O:12][CH3:13])[CH2:14][O:15][CH2:16][O:17][CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: COCOCC(N)(COCOC)c1cccc(Br)n1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCOCC(COCOC)(NC(=O)CCl)c1cccc(Br)n1
Reaction time: 0.17 h

Procedure:
To a solution of 1-(6-bromo-pyridin-2-yl)-2-methoxymethoxy-1-methoxymethoxymethyl-ethylamine (15.0 g, 44.75 mmol) in DCM (150 ml) was added aqueous Na2CO3 solution (10.91 g, 102.925 mmol in water, 30 ml) was added at 0° C. and stirred for 10 min. Chloroacetylchloride (5.56 g, 49.225 mmol) was added to the resultant reaction mixture at 0° C. stirring continued for 1 h at ambient temperature. Reaction mixture was diluted with DCM (˜1 l), and worked up the reaction mixture by washing with water, brine and dried over anhy. Na2SO4. Organic layer was separated and concentrated under reduced pressure to obtain title compound as a brown liquid. Yield=9.0 g (48%). TLC (50% ethyl acetate in hexane) Rf=0.54; LCMS: RtH7=1.341, [M+1]=411.0 and 413.0; HPLC: RtH9=4.27 min (50.4%); 1H NMR (400 MHz, CDCl3): δ 8.11 (d, 1H), 7.57-7.52 (m, 1H), 7.46-7.37 (m, 2H), 4.59-4.52 (m, 4H), 4.23-4.17 (m, 4H), 4.09-4.04 (m, 2H), 3.21 (s, 6H).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[S:8][C:7]([CH3:9])=[N:6][N:5]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[S:8][C:7]([CH3:9])=[N:6][N:5]=1
Reactant: [I-]
Reactant: Cc1nnc(SCCl)s1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nnc(SCI)s1
Temperature: 55 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 5-chloromethylthio-2-methyl-1,3,4-thiadiazole (730 mg: 4 mMol.) in acetone (6 ml) is added sodium iodide (1.2 g: 2.0 equivalents: 8 mMol.), and the mixture is stirred at 55° C. for 2 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and concentrated to give 5-iodomethylthio-2-methyl-1,3,4-thiadiazole (1.05 g) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:20])[C:11]=1[O:21]COC)=[O:9])([CH3:6])[CH3:5].B(Cl)(Cl)Cl>ClCCl.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:25])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:20])[C:11]=1[OH:21])=[O:9])([CH3:6])[CH3:5]
Reactant: COCOc1c(C(=O)NC(C)(C)C(=O)OC)ccc2c(F)cccc12
Agent: ClB(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2c(F)cccc2c1O
Temperature: -67.5 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a stirred solution of 0.107 g of 2-{[5-fluoro-1-(methoxymethoxyl)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 3 ml of dichloromethane at −65 to −70° C. was added by syringe 0.344 ml of 1M BCl3 in dichloromethane. The mixture was stirred for 10 minutes at −65 to −70° C. after which it was allowed to warm to RT and stirred at RT for 0.5 h. The mixture was poured into brine, extracted twice with ethyl acetate, dried, filtered and concentrated to an oil, which was chromatographed on silica gel eluting with ethyl acetate/dichloromethane/heptane to provide 0.088 g of 2-{[5-fluoro-1-(hydroxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][CH3:16])[N:3]=[CH:2]1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]([N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[O:20]
Reactant: CCc1cccc(C)c1NCc1cscn1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: CCc1cccc(C)c1N(Cc1cscn1)C(=O)CCl

Procedure:
A mixture of 3.5 g N-(thiazol-4-yl)methyl-2-ethyl-6-methylaniline (from Example 11) and 125 ml toluene was heated to reflux and 1.7 g chloroacetyl chloride was added dropwise. The mixture was refluxed for 2 hours, cooled, stripped and purified on a silica-gel column using methylene chloride followed by 2% methanol:methylene chloride. C15H17ClN2O5 : calc., %C 58.35, %H 5.51, %N, 9.08; found, %C 57.07, %H 5.58, %N 7.81.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][CH2:21][CH:20](O)[CH2:19]2)[N:13]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][CH2:21][C:20]3([O:5][CH2:1][CH2:2][O:3]3)[CH2:19]2)[N:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC1CCN(c2cccc(Br)n2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Brc1cccc(N2CCC3(C2)OCCO3)n1

Procedure:
Then, to a solution of 2.8 ml of oxalyl chloride in 100 ml of dichloromethane were added dropwise 4.6 ml of dimethyl sulfoxide in a dry ice-acetone bath while stirring, a solution of 5.9 g of the 2-bromo-6-(3-hydroxypyrrolidin-1-yl)pyridine in 50 ml of dichloromethane and finally 17 ml of triethylamine, and the temperature was returned to room temperature over 1 hour. The reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. To the residue were added 50 ml of toluene, 7 ml of ethylene glycol and a catalytic amount of p-toluenesulfonic acid monohydrate, followed by heating under reflux for 3 hours while removing water. After cooling, it was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography with 5–7% ethyl acetate/hexane, to give 6.3 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:23][O:24][CH:25]1[CH2:28][N:27]([CH2:29][CH2:30][NH2:31])[CH2:26]1>COCCOC>[CH3:23][O:24][CH:25]1[CH2:28][N:27]([CH2:29][CH2:30][NH:31][C:2]2[N:3]=[N+:4]([O-:15])[C:5]3[CH:14]=[C:13]4[C:9]([CH2:10][CH2:11][CH2:12]4)=[CH:8][C:6]=3[N:7]=2)[CH2:26]1
Reactant: COC1CN(CCN)C1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC1CN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Yield: 47 %

Procedure:
A solution of chloride 21 (1.32 g, 6.0 mmol), Et3N (1.65 mL, 11.8 mmol) and 2-(3-methoxy-1-azetidinyl)ethylamine (277) (950 mg, 7.3 mmol) in DME (30 mL) was heated at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (4×50 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 34 (890 mg, 48%) as a yellow solid: mp 139-141° C.; 1H NMR δ 8.06 (s, 1H, H-9), 7.38 (s, 1H, H-5), 5.67 (br s, 1H, NH), 4.04 (p, J=5.8 Hz, 1H, CHO), 3.63-3.69 (m, 2H, CH2N), 3.47 (dt, J=5.9, 5.6 Hz, 2H, CH2N), 3.26 (s, 3H, OCH3), 2.93-3.03 (m, 6H, H-6, H-8, CH2N), 2.74 (t, J=5.9 Hz, 2H, NCH2), 2.14 (p, J=7.4 Hz, 2H, H-7); 13C NMR δ 158.7, 154.5, 148.7, 143.3, 129.8, 120.6, 114.6, 70.0, 61.4 (2), 58.0, 56.0, 39.3, 33.1, 32.3, 25.7; MS (APCI) m/z 316 (MH+, 100%). Anal. calcd for C16H21N5O2.¼H2O: C, 60.1; H, 6.8; N, 21.9. Found: C, 60.0; H, 6.6; N, 21.7%.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:25])(=[O:24])[NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[CH:7]=1.CO>>[O:19]1[C:18]2[CH:22]=[CH:23][C:15]([CH2:14][NH:13][S:12]([C:8]3[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=3)(=[O:25])=[O:24])=[CH:16][C:17]=2[O:21][CH2:20]1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-{3-[(benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid methyl ester (0.47 g, 1.25 mmol) in methanol (6 ml) 1N NaOH solution (3.75 ml, 3.75 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.39 g, 87%).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[C:20]([CH3:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10]1)=O)(C)(C)C.CC1C2C(S([Cl:43])(=O)=O)=CC=CC=2C=NC=1.C(OC(NC1CCNC1)=O)(C)(C)C>>[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[C:20]([CH3:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10]1.[ClH:43]
Reactant: Cc1cncc2cccc(S(=O)(=O)N3CCCC(NC(=O)OC(C)(C)C)C3)c12
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Agent: CC(C)(C)OC(=O)NC1CCNC1
Product: Cc1cncc2cccc(S(=O)(=O)N3CCCC(N)C3)c12
Product: Cl

Procedure:
(R/S)-3-(tert-Butoxycarbonylamino)-1-(4-methyl-5-isoquinolinesulfonyl)-piperidine can be prepared by using 4-methyl-5-isoquinolinesulfonyl chloride instead of 4-bromo-5-isoquinolinesulfonyl chloride, and 3-(tert-butoxycarbonylamino)pyrrolidine instead of (S)-3-(tert-butoxycarbonylamino)pyrrolidine in the method of Example 1-1, and then the protective group of the resultant can be removed according to the method described in Example 1-1, Step B to obtain the title compound as hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=O)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].Br[CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C(OC)=O.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[C:5]2[O:12][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(Cl)cc(C=O)c1O
Reactant: COC(=O)C(Br)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cc2cc(-c3ccccc3)oc12
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A mixture of 3.0 g of methyl 5-chloro-3-formyl-2-hydroxybenzoate, 3.44 g of methyl α-bromophenylacetate, 8.28 g of potassium carbonate and 50 ml of dimethylformamide is heated at 70°-80° C. for 15 minutes and further heated at 100° C. for 10 minutes. After cooling, water is added to the mixture, and the aqueous mixture is acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is dissolved in 50 ml of ethanol, and 4.5 g of potassium hydroxide are added to the solution. The mixture is refluxed for 1 hour and then evaporated to remove solvent. Water is added to the residue, and the aqueous mixture is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated to remove solvent. 150 ml of xylene and 30 mg of p-toluenesulfonic acid are added to the residue and the mixture is refluxed for 1 hour. The reaction mixture is evaporated to remove solvent and the residue is dissolved in ethyl acetate. The solution is washed, dried and evaporated to remove solvent. The residue is crystallized from isopropyl ether to give 2.32 g of 5-chloro-2-phenylbenzofuran-7-carboxylic acid.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][C:10](=O)[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:15].C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:25]>>[Cl:15][C:10]1[N:9]=[C:8]([Cl:25])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][N:11]=1
Reactant: O=c1[nH]cc(-c2ccccc2)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cl
Solvent: CCN(CC)CC
Product: Clc1ncc(-c2ccccc2)c(Cl)n1
Yield: 100 %

Procedure:
To 5-Phenyl-1H-pyrimidine-2,4-dione (110 mg, 0.585 mmol) and triethyl amine hydrochloride (317 mg, 2.3 mmol) was added POCl3 (15 mL) and the solution was heated to 120 C for 72 h. POCl3 was removed in vacuum and the resulting brown oil was quenched with ice water and treated with saturated NaHCO3, extracted with ethyl acetate, washed with brine, dried (Na2SO4) to give 2,4-Dichloro-5-phenyl-pyrimidine 131 mg (100% yield). HPLC tr=7.09 min (100%), FIA-MS 224.9 (M+H), HNMR (500 MHz, CDCl3) δ8.49 (1H, s), 7.45 (3H, m), 7.35 (2H, m).
Reaction SMILES: C([N:3](CC)CC)C.[N:8]1([CH2:14][CH2:15][CH2:16]N)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl[C:19]1[C:24]2[O:25][CH2:26][C:27](=[O:29])[NH:28][C:23]=2[N:22]=[C:21]([CH3:30])[N:20]=1>C1C=CC=CC=1>[CH3:30][C:21]1[N:20]=[C:19]([CH2:16][CH2:15][CH2:14][N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[C:24]2[O:25][CH:26]([NH2:3])[C:27](=[O:29])[NH:28][C:23]=2[N:22]=1
Reactant: NCCCN1CCOCC1
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1nc(CCCN2CCOCC2)c2c(n1)NC(=O)C(N)O2
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture of 0.7 ml of triethylamine and 1.44 g of 3-(4-morpholinyl)-1-propylamine is added in the course of 8 hours to a mixture containing 2 g of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one and 1.4 ml of triethylamine in 5 ml of abs. benzene while stirring and refluxing. Then the mixture is refluxed under stirring for 8 hours, evaporated, the residue is taken up with 16 ml of water, triturated, filtered and washed with water and ether to give 1.1 g (36%) of the aimed product, m.p.: 165°-168° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:17][O:16][CH:3]([O:2][CH3:1])[C:4]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CO)CCCN2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 10 g, 38.2 mmol) in MeOH (120 ml) and DCM (60 ml) was added NaBH4 (1.16 g, 30.6 mmol). The reaction mixture was stirred at room temperature for 30 min, then slowly quenched with sat. aq. NH4Cl and concentrated until the organic solvents had been mostly removed. The resulting mixture was extracted with DCM (4×). The combined organic phases were dried over
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:22])=[C:18]([Cl:21])[N:19]=3)[C:14](=[O:23])[C:13]([C:24]([O:26]CC)=[O:25])=[CH:12]2)[C:5]([F:10])=[C:6]([F:9])[C:7]=1[F:8].C(O)(=O)C.ClC(Cl)C>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:22])=[C:18]([Cl:21])[N:19]=3)[C:14](=[O:23])[C:13]([C:24]([OH:26])=[O:25])=[CH:12]2)[C:5]([F:10])=[C:6]([F:9])[C:7]=1[F:8]
Reactant: CCOC(=O)c1cn(-c2cc(N)c(F)c(F)c2F)c2nc(Cl)c(F)cc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
Ethyl 1-(3-amino-4,5,6-trifluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (600 mg) was dissolved in 30 ml of methanol, 10 ml of acetic acid, and 30 ml of dichloroethane, to which was added 100 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred overnight at room temperature. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. To the residue were added 4 ml of acetic acid and 1 ml of hydrochloric acid. The solution was heated at 100° C. and stirred overnight. The reaction solution was concentrated in vacua whereupon diethyl ether was added to the residue. The solid was collected by filtration and washed with diethyl ether to give 160 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[C:16]([C:18]1[CH:19]=[N:20][C:21]([NH2:25])=[CH:22][C:23]=1[NH2:24])#[N:17].O>CO>[NH2:24][C:23]1[C:18]([C:16]#[N:17])=[CH:19][N:20]2[CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:25]=[C:21]2[CH:22]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: N#Cc1cnc(N)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cn2cc(-c3ccccc3)nc2cc1N

Procedure:
2-Bromoacetophenone (1.11 g, 5.6 mmol) and NaHCO3 (470 mg) were added to a solution of 3-cyano-4,6-diaminopyridine (500 mg, 3.7 mmol) in methanol (7.5 ml), and the mixture was heated to reflux overnight. The mixture was cooled, water (4 ml) was added, and the precipitate was filtered to give a first crop of the desired product. The filtrate was evaporated, taken up in ethyl acetate and washed (water, brine). The organic layer was dried (Na2SO4), evaporated, and the residue was purified by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40) to yield a second crop of product. The combined isolates were dried to give the title compound (350 mg, 40%). MS (m/e)=235.1 [M+H+].
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:22])=[C:11](B3OCC(C)(C)CO3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[C:30]1[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([NH:38][CH3:39])=[O:37])=[CH:32][CH:31]=1>>[Cl:22][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH:3]=[O:4])=[CH:6][NH:7]2)=[CH:12][C:11]=1[C:30]1[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([NH:38][CH3:39])=[O:37])=[CH:32][CH:31]=1
Reactant: CNC(=O)COc1ccc(Br)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNC(=O)COc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Temperature: 90 °C
Yield: 72.9 %

Procedure:
To the slurry of methyl-6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (240 mg, 1.0 mmol) was added 2 M potassium carbonate (2.5 mL, 5.0 mmol), 2-(4-bromophenoxy)-N-methylacetamide (240 mg, 1.00 mmol) and PddppfCl2 (50 mg, 0.061 mmol). The sealed vial was heated to 90° C. for 30 min. The reaction was cooled to room temperature and quenched with water (20 mL), and then washed three times with ethyl acetate (20 mL). The combined organics were dried and concentrated to give the title compound (250 mg, 55% yield) as a yellow solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.37 (d, 1H), 8.02 (s, 1H), 7.68 (s, 1H), 7.38 (d, 2H), 7.05 (d, 2H), 4.52 (s, 2H), 2.68 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.Cl.[NH2:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:15]([NH:17][CH:18]1[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:11][C:12]2[CH:13]=[C:14]([C:15](=[O:16])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1csc(Br)c1

Procedure:
Compound a was prepared by coupling commercially available 5-bromothiophene-3-carboxylic acid with 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO 04/071440) using the method described in Example 128 to afford a tan solid. HPLC Ret time=3.02 min. LCMS [M+H]+ 379.0.
Reaction SMILES: [N:1]1([C:5]2[C:6]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[N:1]1([C:5]2[C:6]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of methyl 3-(azetidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (60 mg, 0.18 mmol) in methanol (20 mL) was added sodium hydroxide (50 mg, 1.25 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (3N), and the product was precipitated and filtered to give 3-(azetidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (35.3 mg, 61%).