Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6](F)[CH:7]=1.[CH3:13][NH2:14].C1COCC1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[NH:14][CH3:13]
Reactant: Cc1cc(Br)cc(F)c1[N+](=O)[O-]
Reactant: CN
Solvent: C1CCOC1
Product: CNc1cc(Br)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99 %

Procedure:
A MW vial was charged with 5-bromo-1-fluoro-3-methyl-2-nitrobenzene (500 mg, 2.137 mmol) and methylamine 2M in THF (5 mL, 10.0 mmol). The MW vial was sealed and the reaction mixture was submitted to MW irradiation for 30 min at 100° C. The reaction was cooled down to RT and concentrated under reduced pressure to afford the title product (520 mg, 2.122 mmol, 99% yield) as yellow solid. tR: 1.19 min (LC-MS 2); ESI-MS: no ionisation (LC-MS 2).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][O:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:32][CH2:31]1>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:43][C:42]4[CH:44]=[CH:45][C:39]([O:38][CH2:37][CH2:36][N:33]5[CH2:32][CH2:31][O:30][CH2:35][CH2:34]5)=[CH:40][CH:41]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(OCCN5CCOCC5)cc4)cc3n2C(=O)OC(C)(C)C)cn1

Procedure:
The title compound was prepared from tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10) (100 mg, 0.216 mmol) and 4-(2-morpholinoethoxy)aniline (58 mg, 0.26 mmol, 1.2 eq) using the method described in Preparation 35 and using silica gel column chromatography eluting with EtOAc:hexane:triethylamine 10:10:1 (20 mg, 15%). 1H-NMR (500 MHz, CDCl3) 1.45 (s, 9H), 1.67 (s, 9H), 2.58 (m, 4H), 2.8 (t, J=5.8 Hz, 2H), 3.73 (m, 4H), 4.11 (t, J=5.8 Hz, 2H), 6.54 (s, 1H), 6.6 (s, 1H), 6.91 (d, J=8.9 Hz, 2H), 7.27 (d, J=8.9 Hz, 2H), 7.37 (s, 1H), 7.8 (s, 1H), 8.19 (s, 1H), 8.39 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1.N(C(OCC)=O)=NC(OCC)=O>CO.C1C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(F)cc1OC1CCN(C)CC1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (12 g, 70.5 mmol), triphenyl-phosphine (22.2 g, 84.6 mmol), N-methyl-4-hydroxypiperidine (8.1 g, 70.3 mmol) and benzene (25 mL) was heated until all the solids dissolved. The solution was cooled to 0° C., then sonicated while adding diethyl azodicarboxylate (14.7 g, 84.6 mmol) dropwise. After the addition was complete, the reaction was sonicated for an additional 60 minutes, and then purified by flash chromatography, eluting sequentially with 50% EtOAc in hexanes followed by 1%, 2%, 5% then 10% MeOH in CHCl3, to yield 10.8 g (40.4 mmol, 57%) of an oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].O.NN>C(O)C>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH2:24])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OC2CCN(CCN3C(=O)c4ccccc4C3=O)CC2)c2ncccc2c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCc1cc(OC2CCN(CCN)CC2)c2ncccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.8 %

Procedure:
2-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)-1H-isoindole-1,3(2H)-dione (for example, as prepared for Intermediate 30) (2.76 g, 6.03 mmol) was stirred under nitrogen in ethanol (40 ml) containing hydrazine monohydrate (commercially available, for example, from Aldrich) (0.71 ml, 15.1 mmol) at 80° C. for 2 h. The reaction was cooled with ice-water and filtered. The filter-cake was leached with ethanol and the combined filtrates were evaporated to an oil containing a white solid. This solid was mixed with DCM (about 20 ml) and filtered. The filter-cake was leached with more DCM and the combined filtrates were evaporated to give the title compound (2.07 g) as an oil: LCMS RT=2.32 min, ES+ve m/z 328 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[CH:14][C:13]=1[CH2:29][OH:30].C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:22][CH:23]=2)=[CH:14][C:13]=1[CH:29]=[O:30]
Reactant: OCc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1Br
Temperature: 25 °C

Procedure:
DMSO (0.69 mL, 9.72 mmol) was added dropwise to oxalyl chloride (0.42 mL, 4.86 mmol) in 4 mL DCM at −78° C. After 20 minutes a DCM solution (6 mL) of the intermediate from Step C (1.2 g, 3.47 mmol) was added dropwise. After stirring for 15 minutes at −78° C. triethylamine (2.42 mL, 17.35 mmol) was added. The reaction mixture was then allowed to warm to room temperature. The solution was partitioned between aqueous saturated NH4Cl and DCM. The organic phase was washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 10.43 (s, 1H); 8.12 (d, J=2.4 Hz, 1H); 7.75 (d, J=8.6 Hz, 1H); 7.67-7.65 (m, 1H); 7.63 (d, J=8.5 Hz, 2H); 7.34 (d, J=8.5 Hz, 2H). LCMS1 4.09 min. (M+H)=345
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C2C=CC=C(C(Cl)=O)C=2C=CC=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]([CH3:36])=[C:34]([CH3:37])[S:33][C:32]1=[NH:38].CCN(CC)CC>C1COCC1>[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]([CH3:36])=[C:34]([CH3:37])[S:33]/[C:32]/1=[N:38]\[C:11]([C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(O)c1cccc2ncccc12
Agent: O=C(Cl)c1cccc2ncccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2ncccc12
Yield: 48.2 %

Procedure:
The quinoline-5-carboxylic acid (Lancaster, 0.25 g, 1.4 mmol) was converted to quinoline-5-carbonyl chloride using 5 mL SOCl2 using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and quinoline-5-carbonyl chloride in 30 mL THF were processed as in Example 134B to afford the title compound (0.18 g, 0.53 mmol, 49% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.30 (d, J=0.7 Hz, 3H), 2.34 (s, 3H), 3.31 (s, 3H), 3.80 (t, J=5.1 Hz, 2H), 4.49 (t, J=5.3 Hz, 2H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.83 (dd, J=8.5, 7.1 Hz, 1H), 8.15 (dt, J=8.5, 1.0 Hz, 1H), 8.40 (dd, J=7.3, 1.2 Hz, 1H), 8.87 (dd, J=4.1, 1.7 Hz, 1H), 9.55 (ddd, J=8.8, 1.7, 0.7 Hz, 1H); MS (DCI/NH3) m/z 342 (M+H)+; Anal. calculated for C18H19N3O2S: C, 63.32; H, 5.61; N, 12.31. Found: C, 63.44; H, 5.05; N, 12.10.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[C:14]1(/[CH:20]=[CH:21]/B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:21]=[CH:20]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Reactant: OB(O)/C=C/c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1Cc2c(/C=C/c3ccccc3)ccc(N)c2C1=O

Procedure:
A mixture of 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.0 g, 4.1 mmol), E-phenylethenylboronic acid (921 mg, 6.22 mmol), potassium carbonate (1.72 g, 12.4 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (169 mg, 0.207 mmol) in 10 mL 1,4-Dioxane and 2.5 mL H2O was irradiated in a microwave reactor at 100° C. for 30 minutes. The crude mixture was partitioned between EtOAc and sat. NaHCO3. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. MS (ES+): m/z 265.31 (100) [MH+]; HPLC: tR=1.24 min (UPLC, Analytical).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:17]1([C:23]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:24]=2[C:25](Cl)=[O:26])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:25]([C:24]3[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=[CH:31][C:23]=3[N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:26])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 1-(4-Methanesulfonyl-phenyl)-piperazine and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (76%, yellow solid, MS (m/e): 475.1 (M+H, 100%)
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:10][CH:11]=2)[C:6](=[O:24])[N:5]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:2]=[CH2:3].[Cl:32][C:33]1[C:38]([C:39](Cl)=[O:40])=[C:37]([Cl:42])[N:36]=[CH:35][N:34]=1>C(Cl)Cl>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:18])[CH3:19])[C:39]([C:38]3[C:33]([Cl:32])=[N:34][CH:35]=[N:36][C:37]=3[Cl:42])=[O:40])=[CH:10][CH:11]=2)[C:6](=[O:24])[N:5]1[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: C=CCn1c2ccc(NCCO[Si](C)(C)C(C)(C)C)cc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Product: C=CCn1c2ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c3c(Cl)ncnc3Cl)cc2c(=O)n1Cc1ccccc1
Reaction time: 6 h
Yield: 46.4 %

Procedure:
To a stirred, cooled (0° C.) solution of product of 11E (0.55 g, 1.23 mmol) and TEA (0.5 g, 5.0 mmol) in DCM (12 mL) was added drop wise a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (0.26 g, 1.23 mmol) in DCM (5 mL). After 6 h, the reaction was concentrated in vacuo, diluted with ethyl acetate, and washed with water (2×10 mL) and saturated aqueous brine. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford oil. The residue was purified by flash chromatography using 12% ethyl acetate in hexane as eluent to afford title compound (0.35 g, 46%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 7.75 (s, 1H), 7.46 (m, 3H), 7.36 (m, 4H), 5.94 (m, 1H), 5.34 (s, 2H), 5.08 (m, 1H), 4.96 (m, 1H), 4.82 (m, 2H), 4.0 (m, 2H), 3.77 (t, J=4.8 Hz, 2H), 0.8 (s, 9H), 0.01 (s, 6H); ESI-MS m/z=611 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([NH2:16])=[CH:11][CH:12]=3)[C@@:7]3([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]3)[C:6]=2[CH:5]=[C:4]([O:23]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:22][C:18]1[O:19][CH2:20][CH2:21][C@@:7]2([N:17]=1)[C:6]1[CH:5]=[C:4]([OH:23])[CH:3]=[C:2]([F:1])[C:15]=1[O:14][C:13]1[C:8]2=[CH:9][C:10]([NH2:16])=[CH:11][CH:12]=1
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(N)ccc1O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c(F)cc(O)cc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
The crude (S)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (1.196 g, 3.63 mmol) was dissolved in dcm (100 mL) and the solution was cooled to 0° C. A DCM solution of boron tribromide (14.53 mL, 14.53 mmol) was added, and the reaction was warmed to RT. After 1.5 h, the reaction was quenched with 120 mL of 10:1 saturated NH4Cl and commercial NH4OH. The mixture was extracted with 5% MeOH-DCM (3×250 mL). The organics were combined, washed with dilute brine (50 mL), dried over MgSO4 and concentrated, affording 0.97 g of crude (S)-2,7′-diamino-4′-fluoro-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2′-ol, which was used without purification in the next step. MS m/z=316 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.C(OCC)(=O)C>[Si:23]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Methyl (2S,4R)-N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (22.1 g, 82.6 mmol) was dissolved in dry DMF (100 mL) under nitrogen. Imidazole (16.8 g, 248 mmol) was added and the mixture cooled to 0° C. tert-Butyldimethylsilyl chloride (13.1 g, 86.7 mmol) was added in small portions and then the mixture was allowed to warm to room temperature. After stirring overnight, the mixture was diluted with 300 mL ethyl acetate and washed with water three times (500 mL, 200 mL, 200 mL). The organic extracts were washed one final time with brine and then dried over MgSO4, filtered and concentrated to give 29.5 g (99%) of desired product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[NH:33][C:34]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21])=[O:35]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1N
Product: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 73 %

Procedure:
Using Method F2 with 8-(4-amino-3-(methylthio)phenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 2-fluoro-5-trifluoromethylphenyl isocyanate, the title compound (37 mg, 73%) was obtained as a powder.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15]1[CH:19]=[C:18]([O:20][CH:21]([F:23])[F:22])[N:17]([CH3:24])[N:16]=1>ClC(Cl)(Cl)Cl>[Cl:4][C:19]1[C:15]([C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([Cl:13])=[CH:12][C:7]=2[Cl:6])=[N:16][N:17]([CH3:24])[C:18]=1[O:20][CH:21]([F:22])[F:23]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(Cl)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Reaction time: 2 h

Procedure:
16.9 g (125 mmol) of sulfuryl chloride were added dropwise to a solution of 35 g (114 mmol) of 3-(2,4-dichloro-5-methylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 120 ml of tetrachloromethane. After the reaction mixture had been stirred for 2 hours, it was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate, filtered and concentrated. Yield: 30.8 g.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[BH4-].[Na+]>CO>[C:1]([NH:9][NH:10][CH:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CN1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(NNC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
272 g (2 mol) of benzoic acid hydrazide are added to 1500 ml of methanol with stirring. Over 1 hour, 226 g (2 mol) of 1-methyl-4-piperidinone are then added dropwise at a temperature of 30° C. Slight cooling is necessary. The reaction mixture is stirred for half an hour at 30° C. and then for a further 1 hour at 60° C. The solution is then cooled to 0° C. and over a period of 2 hours 68 g (1.8 mol) NaBH4 is added using a spatula (strong foaming). Towards the end of the addition the mixture is warmed to room temperature. The solvent is evaporated off using a rotary evaporator and to the residue 900 g ice and 1000 ml dichloromethane are added with stirring. The organic phase is separated using a separating funnel and the aqueous phase is shaken twice with 300 ml dichloromethane in each case. The combined organic fractions are dried over MgSO4, the dichloromethane evaporated off and the residue recrystallized in 1 liter of isopropanol with the addition of 10 g active charcoal. The reaction product is dried in a drying cupboard at 50° C. in vacuo. (M.p. 149°-150° C.).
Reaction SMILES: [Cr]([O-])(OCl)(=O)=O.[NH+]1C=CC=CC=1.[OH:13][CH:14]1[CH2:17][CH:16]([S:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])=[O:19])[CH2:15]1.C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[O:13]=[C:14]1[CH2:17][CH:16]([S:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])=[O:19])[CH2:15]1
Reactant: CCCCOS(=O)(=O)C1CC(O)C1
Agent: O=[Cr](=O)([O-])OCl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCOS(=O)(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
Pyridinium chloro chromate (10.3 g, 48.07 mmol) was added to a cooled solution of butyl 3-hydroxycyclobutane-1-sulfonate (5 g, 24.03 mmol) in dry DCM (50 mL) at 0° C. The resulting reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC (40% ethyl acetate in hexane). The reaction mixture was diluted with DCM, filtered and the filtrate was concentrated to afford the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 2.8 g of the product (58% yield).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.[CH2:19](O)[CH3:20]>>[NH2:5][C:6]1[C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][CH:7]=1
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(N)c2c1OCCO2
Temperature: -40 °C
Reaction time: 1 h

Procedure:
23.5 g (0.198 mol) of thionyl chloride are introduced slowly into a 2 1 three-necked round-bottomed flask containing 772 ml of ethanol cooled to −40° C., with stirring, the stirring is continued at this temperature for 1 h, 38.6 g (0.198 mol) of 8-amino-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid dissolved in 100 ml of ethanol are added slowly, over 15 min, and the mixture is allowed to warm to room temperature overnight.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C(O)c2ccc(N)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-5-methylpyridine (3.0 g) and sodium azide (4.97 g) in DMSO (60 ml) was stirred for 24 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (3.39 g) in THF (40 ml) was added dropwise to a suspension of aluminum lithium hydride (1.06 g) in THF (40 ml) at 0° C. The mixture was stirred at room temperature for 1 hour, and water (1.06 ml), 15% aqueous solution of sodium hydroxide (1.06 ml) and water (3.18 ml) were sequentially and slowly added dropwise to the solution at 0° C. The mixture was stirred for 64 hours at room temperature, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized, to give (4-aminophenyl)(5-methylpyridin-2-yl)methanol (2.07 g) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][S:6][CH2:7][C:8]1[O:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].I([O-])(=O)(=O)=[O:15].[Na+]>CO.O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][S:6]([CH2:7][C:8]1[O:12][CH:11]=[CH:10][CH:9]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)CSCc1ccco1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CS(=O)Cc1ccco1

Procedure:
2.00 g of ethyl-2-(furfurylthio)acetate was dissolved in 40 ml of methanol, and stirred under cooling in an ice bath. 2.50 g of sodium metaperiodate dissolved in 20 ml of water was added dropwise, and stirred overnight at room temperature. The reaction product was extracted by adding 100 ml of dichloromethane, and washed with water. Dichloromethane was evaporated in vacuo, and the residue was purified by column chromatography using benzene:ethyl acetate=4:1 as developing solvent to obtain the captioned ethyl-2-(furfurylsulfinyl)acetate. Yield: 1.93 g.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([C:12](=[O:16])[CH2:13][CH2:14]Br)[CH2:5]3)[CH2:2]1)[CH2:9]2.Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([C:12](=[O:16])[CH2:13][CH2:14][N:28]4[CH2:29][CH2:30][N:25]([C:20]5[N:19]=[CH:24][CH:23]=[CH:22][N:21]=5)[CH2:26][CH2:27]4)[CH2:5]3)[CH2:2]1)[CH2:9]2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(CCBr)N1CC2CC3CC(C2)CC1C3
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCN1CCN(c2ncccn2)CC1)N1CC2CC3CC(C2)CC1C3
Reaction time: 2 h
Yield: 31 %

Procedure:
A solution of 1-(4-azatricyclo[4.3.1.1(3,8)]undec-4-yl)-3-bromo-1-propanone (2.00 g, 6.99 mmol), 1-(2-pyrimidinyl)piperazine dihydrochloride (1.66 g, 7.00 mmol), diisopropylethylamine (3.6 mL, 21 mmol) in anhydrous dimethylformamide (100 mL) was heated at 60° C. for 23 hours. The reaction mixture was poured into water (700 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried, preadsorbed into silica gel, and purified by flash chromatography (8 cm diameter, elution with 2.5% methanol in dichloromethane). The resulting solid was stirred over hexane for 2 hours and filtered to yield a beige solid (800 mg, 31%, m.p. 117°-119° C.).