Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3][CH:4]=1
Reactant: Nc1ccccc1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccccc3)ncc2Cl)CC1
Temperature: 120 °C
Yield: 46 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.080 g, 0.24 mmol) in 1,4-dioxane (1.0 mL) containing aniline (0.043 mL, 0.48 mmol) and p-toluenesulfonic acid (4.5 mg, 0.024 mmol) was heated under microwave irradiation at 120° C. for 4 hours. The reaction mixture was adsorbed onto silica gel and purified by silica column chromatography (Combiflash Rf, 12 g SiO2 Cartridge, 20-50% EtOAc in cyclohexane) to give the title product 23 as a light yellow foam (0.044 g, 46%). LCMS-B: rt 7.718 min; m/z 393 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[CH:4][N:3]=1.[IH:10]>C(Cl)Cl>[I:10][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: I
Reactant: CSc1cc(Cl)ncn1
Solvent: ClCCl
Product: CSc1cc(I)ncn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-chloro-6-methylsulfanyl-pyrimidine 34 (0.54 g, 3.36 mmol) and 57% hydriodic acid solution (2.50 mL, 18.95 mmol) in DCM (3 mL) is stirred at room temperature. After 5 h, the solid is collected by filtration and washed with DCM. The cake is dissolved in water (10 mL) and basified with saturated NaHCO3 solution to pH=8. The aqueous layer is extracted with DCM (2×50 mL). The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated to afford the desired product 4-iodo-6-methylsulfanyl-pyrimidine 35.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[CH:10][C:9]2[C:5](=[CH:6][C:7](=[O:12])[N:8]=2)[CH:4]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[C:15]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:11][CH:10]=2)[CH2:6][C:7]1=[O:12])(=[O:17])[CH3:16]
Reactant: O=C1C=c2cc(C(F)(F)F)ccc2=N1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(=O)N1C(=O)Cc2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
2.0 g of 5-trifluoromethyloxoindole were dissolved in 25 ml of xylene, 2.41 ml of acetic anhydride were added and the mixture was heated to boiling under reflux for 5 hours. The reaction solution was cooled to room temperature and diluted with 150 ml of ethyl acetate, and washed with 80 ml each of water, saturated sodium bicarbonate solution and saturated NaCl solution. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified on silica gel with the eluent n-heptane=>n-heptane/ethyl acetate=3:1. This gave 1.74 g of 1-acetyl-5-trifluoromethyl-1,3-dihydroindol-2-one as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[S:10](=[O:12])(=[O:11])[N:9]=[C:8](OCC)[C:7]=2[CH:16]=1.[CH3:19][N:20]([CH2:22][C:23]1[O:27][C:26]([CH2:28][S:29][CH2:30][CH2:31][NH2:32])=[CH:25][CH:24]=1)[CH3:21]>C1(C)C=CC=CC=1>[CH3:21][N:20]([CH2:22][C:23]1[O:27][C:26]([CH2:28][S:29][CH2:30][CH2:31][NH:32][C:8]2[C:7]3[CH:16]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH3:18])=[CH:5][C:6]=3[S:10](=[O:11])(=[O:12])[N:9]=2)=[CH:25][CH:24]=1)[CH3:19]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CCOC1=NS(=O)(=O)c2cc(OC)c(OC)cc21
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)S(=O)(=O)N=C2NCCSCc1ccc(CN(C)C)o1
Yield: 47.5 %

Procedure:
A toluene (50 ml) solution of 5,6-dimethoxy-3-ethoxy-1,2-benzoisothiazole-1,1-dioxide (D5) (0.13 g) was heated under reflux with 2-[(5-dimethylaminomethylfuran-2-yl)methylthio]ethylamine (0.2 g) for 18 h. Evaporation of the solvent and purification of the residue by column chromatography on silica gel using 5% methanolic chloroform as eluant afforded the title compound (0.1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[C:17]3=[N:18][CH:19]=2)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:46][C@H:47]([OH:48])[CH3:49])[CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=4)(=[O:37])=[O:38])[C:17]3=[N:18][CH:19]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCNCC5)c(F)c4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C[C@@H](C)O)CC5)c(F)c4)cnc32)cc1
Yield: 79 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 179) (170 mg, 0.272 mmol) was alkylated using (S)-2-methyloxirane (32 mg, 0.544 mmol), DIPEA (105 mg, 0.812 mmol) and ethanol (5 mL) to get 147 mg (79% yield) of the titled compound. MS: m/z=684.2 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13]>>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([C:4]([NH2:5])=[N:12][NH:13]2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: NN
Solvent: O
Product: Nc1n[nH]c2cc(F)ccc12
Yield: 37.9 %

Procedure:
To 2,4-difluorobenzonitrile (1.21 g, 8.70 mmol) was added hydrazine monohydrate (8.46 mL, 174 mmol). The mixture was heated to reflux for 5 hours and then poured onto ice. The solution was extracted with ethyl acetate, dried with magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (25-100% ethyl acetate/hexane) to afford 6-fluoro-1H-indazol-3-amine (0.5 g, 3.3 mmol, 38% yield) as light yellow powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 11.42 (s, 1H), 7.70 (dd, J=8.55, 5.49 Hz, 1H), 6.97 (dd, J=10.07, 1.83 Hz, 1H), 6.72-6.79 (m, 1H), 5.40 (s, 2H). MS (LC/MS) R.T.=0.61; [M+H]+=152.11.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][NH:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.Cl[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][N:9]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: CC(C)c1c[nH]c2nc(N)nc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2cc(C(C)C)c3c(Cl)nc(N)nc32)c1C
Temperature: 45 °C
Yield: 20 %

Procedure:
A suspension of 4-chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (105 mg, 0.5 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (93 mg, 0.5 mmol) and K2CO3 (85 mg, 0.6 mmol) in dry DMF (1 mL) was heated to 45° C. overnight, Work-up (EtOAc), evaporation, and purification by preparative TLC (MeOH/CH2Cl2 10:1) gave 4-chloro-5-isopropyl-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (36 mg). HPLC Rt: 5.867 min. 1H-NMR (DMSO-d6): δ 8.07 (s, 1H), 6.74(s, 1H), 6.51 (s, 2H), 5.22 (s, 2H), 3.70 0s, 3H), 3.23 (7, 1H), 2.21 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:5][N:6]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Yield: 90.5 %

Procedure:
A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (50 mg, 0.144 mmol), ethyl 2-bromo-2-methylpropanoate (22 μL, 0.144 mmol) and diisopropylethylamine (76 μL, 0.433 mmol) in DMF (1 mL) was heated to 60° C. for 20 hours. The mixture was then concentrated, sonicated in ethyl ether until fully dissolved, and washed with 1N HCl. The mixture was extracted with diethyl ether (2×5 mL), and the combined organic extracts dried over sodium sulfate, filtered, and concentrated to provide ethyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a brown oil (60 mg, 91%).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:6]=1)=[NH:4].[S:25]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=O)(=[O:28])(=[O:27])[NH2:26]>>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:3]2[N:4]=[C:32]([C:31]3[CH:30]=[C:29]([S:25]([NH2:26])(=[O:28])=[O:27])[CH:37]=[CH:36][CH:35]=3)[O:1][N:2]=2)[N:10]=1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1cccc(-c2nc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)no2)c1

Procedure:
The title compound was prepared from N-hydroxy-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxamidine (example C.2) (0.176 g, 0.5 mmol) and commercially available 3-sulfamoyl-benzoic acid (0.1 g, 0.5 mmol) according to the general procedure V. Obtained as an off-white solid (0.11 g, 42%). MS (ISN) 514.1 [(M−H)−]; mp 205° C.
Reaction SMILES: [CH2:1]([C:8]1([N:29]([CH3:31])[CH3:30])[CH2:13][CH2:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][C:19]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=3)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(O)C.[Pd]>[CH2:1]([C:8]1([N:29]([CH3:31])[CH3:30])[CH2:9][CH2:10][CH:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][C:19]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=3)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C2=CCC(Cc3ccccc3)(N(C)C)CC2)[nH]c2ccc(OC(F)(F)F)cc12
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1c(C2CCC(Cc3ccccc3)(N(C)C)CC2)[nH]c2ccc(OC(F)(F)F)cc12
Reaction time: 4 h

Procedure:
(±)-N-[1-Benzyl-4-(3-methyl-5-trifluoromethoxy-1H-indol-2-yl)cyclohex-3-enyl]-N,N-dimethylamine (230 mg, 0.53 mmol) was dissolved in methanol (40 ml) and ethanol (10 ml), while heating, and Pd/C (5%, 100 mg) was added under argon. Hydrogenation was carried out at 40° C. under 3 bar for 4 h. The catalyst was then filtered off with suction over Celite and the filtrate was concentrated. The solid colourless residue (227 mg) was separated by chromatography [silica gel 60 (30 g); ethyl acetate/methanol (20:1; 400 ml); (4:1; 500 ml) (2:1; 300 ml)]. 1-Benzyl-N,N-dimethyl-4-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)cyclohexanamine (more polar diastereomer) was obtained in a yield of 175 mg (77%) as a colourless solid.
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.O=[C:33]1[CH2:38][CH2:37][CH:36]([O:39][C:40]2[N:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[N:43]=[C:42]([C:50]([OH:52])=[O:51])[CH:41]=2)[CH2:35][CH2:34]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([C@@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][C:40]3[N:45]=[C:44]([C:46]([F:48])([F:47])[F:49])[N:43]=[C:42]([C:50]([OH:52])=[O:51])[CH:41]=3)[CH2:35][CH2:34]2)[CH2:26]1)#[N:29]
Reactant: O=C1CCC(Oc2cc(C(=O)O)nc(C(F)(F)F)n2)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(C(=O)O)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (500.0 mg, 1.036 mmol) and 6-[(4-oxocyclohexyl)oxy]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid in dry 1,2-dichloroethane (14.36 mL, 182.3 mmol) were stirred for 5 minutes and sodium triacetoxyborohydride (898 mg, 4.24 mmol) was added. The reaction mixture was stirred at 25° C. for 16 hours, at which time LCMS analysis showed mainly the two diastereomeric products. The reaction was quenched with water, neutralized with NaHCO3 and extracted with ethyl acetate and the solvent was evaporated. The residue was purified by LCMS (pH 10) and the fractions containing the second peak were combined and evaporated. 1H NMR (400 MHz, CD3OD) δ 8.90 (m, 1H), 8.83 (s, 1H), 8.55 (m, 1H), 7.75 (d, 1H), 7.51 (d, 1H), 7.15 (d, 1H), 5.78 (s, 4H), 5.23 (m, 1H), 3.50-3.70 (m, 3H), 1.40-2.40 (m, 8H). 19F NMR (376 MHz, CD3OD) δ −70.52 (s), −77.53 (s). MS (ES): 698(M+1).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>C(O)CCC>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: C1CNCCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(N2CCCNCC2)cc1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
A solution of homopiperazine (11.4 g, 114 mmol) in 1-butanol (40 mL) was added to a refluxing solution of 1-chloro-4-nitrobenzene (6.0 g, 38 mmol) in 1-butanol (40 mL) over 15 minutes. The mixture was maintained at reflux for 24 hours then cooled to room temperature and extracted with 2N hydrochloric acid. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford 1-(4-nitro-phenyl)-[1,4]diazepane (3.5 g, 42%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8](C(O)=O)[C:7](O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC2N([OH:23])N=NC=2C=1.CC(C)N=C=NC(C)C>>[N+:1]([C:4]1[CH:12]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:23])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: On1nnc2ccccc21
Agent: CC(C)N=C=NC(C)C
Product: O=[N+]([O-])c1ccccc1O

Procedure:
This material was prepared from 5-nitrosalicylic acid (1c) (1 g, 5.46 mmol), HOBt (1 g, 7.4 mmol), DIC (1,3-diisopropylcarodiimide, 1 mL, 6.4 mmol), and an amino PEGA resin (1 g, 0.4 mmol) using a procedure similar to polystyrene resin (PS-2a).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([O:27][CH3:28])[CH:24]=1)[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: NN
Reactant: COc1cc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc(OC)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc(OC)c1
Yield: 90.4 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(3,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (200 mg, 0.48 mmol, prepared in Synthetic Example 23) in DMF (5 ml) was added hydrazine monohydrate (80%, 100 μl, 2.50 mmol, 5.2 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(3,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (179 mg, 90%).
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cccc(-c2ccncc2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from 3-pyridin-4-yl-benzoic acid methyl ester [CAS-No. 126179-78-0] (3.60 g, 16.88 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (3.88 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[S:23](Cl)(=[O:25])=[O:24]>>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:14][S:23]([C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[F:15])(=[O:25])=[O:24])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1
Reactant: Cc1nc(N)ccc1COCC1CC1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Product: Cc1nc(NS(=O)(=O)c2cc(F)ccc2F)ccc1COCC1CC1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-6-methyl-pyridin-2-ylamine (0.053 g) and 2,5-difluoro-benzenesulfonyl chloride (0.059 g) as a light yellow solid (0.063 g). MS (ESI−): 367.0 ([M−H]−)
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:7]2=O.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:7]1[C:6]2[C:11](=[C:2]([F:1])[C:3]([CH3:17])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=1
Reactant: COC(=O)c1cc(=O)c2ccc(C)c(F)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)c2ccc(C)c(F)c2n1
Yield: 75 %

Procedure:
Methyl 8-fluoro-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (7-7, 1.23 g, 5.23 mmol) in POCl3 (11 ml) was heated at 100° C. for 1 hour. The excess POCl3 was removed in vacuo. The resulting residue was triturated with ether, then filtered and washed with ether till no brown color remained in the ether. The remaining solid was Methyl 4-chloro-8-fluoro-7-methylquinoline-2-carboxylate (7-8, 993 mg, 75% yield) 100% pure by LCMS, LRMS m/z (M+H)+ 254.0 found, 254.1 required.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13].[P:15]([O-:23])([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([O:23][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13])=[O:16])[CH3:19]
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1C
Reactant: CCOP(=O)([O-])OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1C(=O)N(COP(=O)(OCC)OCC)S(=O)(=O)N1C
Yield: 66 %

Procedure:
A mixture of 2-chloromethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 4.16 mmol), diethyl phosphate (Formula III: A=B=Et) (0.96 g, 6.63 mmol), tetrabutylammonium bromide (94 mg, 0.29 mmol) and triethylamine (0.63 g, 6.23 mmol) in methylene chloride (20 ml) was allowed to reflux for 24 hours. After adding an additional tetrabutylammonium bromide, the mixture was refluxed for an additional 48 hours, and then cooled. The mixture was purified by silica gel flash chromatography (ethyl acetate/hexane) to afford 0.98 g (66%) of 2-(diethoxyphosphinyloxymethyl)-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: A=B=Et; R1 =H; R2 =propyl; R3 =CH3) as an oil.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[CH2:12][N:13]=1.Cl[CH2:20][C:21]1[O:22][CH:23]=[CH:24][CH:25]=1>CCCCCC.C1COCC1>[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[C@H:12]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:13]=1
Reactant: ClCc1ccco1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccco1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.55M solution of butyllithium (6.45 ml, 10 mmol) in hexane was added by syringe to a stirred solution of (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (1.84 g, 10 mmol) in THF (50 ml) at -78° C. and the solution stirred for 1 hour at -78° C. A solution of 2-chloromethylfuran (1.3 g, 11 mmol) in THF (10 ml) was added gradually and the stirring continued overnight. The solvent was removed under reduced pressure, the residue dissolved in ethyl acetate (50 ml) and extracted with phosphate buffer (pH 7). The water phase was extracted twice with ethyl acetate (2×20 ml ). The organic layer was dried (MgSO4), solvent evaporated under reduced pressure and the residue purified by flash chromatography (diethyl ether/hexane 15/1, silica gel).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=2)[NH2:58])=[CH:51][CH:50]=1>CN(C=O)C>[N:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:56]=[C:57]([NH:58][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)=[CH:51][CH:50]=1
Reactant: Nc1cccc(-c2ccncc2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccncc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 42.1 %

Procedure:
DIEA (0.028 mL, 0.160 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.030 g, 0.146 mmol) and HATU (0.061 g, 0.160 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyridin-4-ylaniline (0.025 g, 0.146 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 42% yield: LCMS (ESI) m/z 359 (MH+).