Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[C:28]1([CH2:34][S:35](Cl)(=[O:37])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:35]([CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:37])=[O:36])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNS(=O)(=O)Cc3ccccc3)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and phenylmethanesulfonyl chloride.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH2:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.CS[C:25]1[NH:26][CH2:27][CH2:28][N:29]=1>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH:21][C:25]2[NH:29][CH2:28][CH2:27][N:26]=2)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: CSC1=NCCN1
Agent: I
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2CNC1=NCCN1
Temperature: 150 °C
Yield: 49.8 %

Procedure:
C-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine (100 mg, 0.31 mmol) and 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydroiodide (76 mg, 0.31 mmol) were added to 2 mL CH2Cl2, and the reaction mixture was heated to gentle reflux until all of the solvent was evaporated. The reaction mixture was heated to 150° C. for 30 minutes and then cooled. The crude mixture was basified by dropwise addition of aqueous NaOH solution, and then purified by preparative liquid chromatography (CH2Cl2/MeOH 90:10) on a short silica gel column. Removal of the solvent afforded 57 mg (47%) of (6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine. MS: 370 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.F[C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:34][N:33]=1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH:42]=[CH:41][N:40]=[N:39]4)=[CH:34][N:33]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Fc1ccc(-n2ccnn2)cn1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCNc3ccc(-n4ccnn4)cn3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (30 mg, 0.11 mmol) from Example 2 step 3 was dissolved in NMP (0.21 mL), DBU (24.4 mg, 0.16 mmol) was added, stirred at room temperature for 10 minutes. 2-fluoro-5-(1H-1,2,3-triazol-1-yl)pyridine (21 mg, 0.13 mmol; from step 2 of this example) was added. Reaction was heated to 110° C. for 3 hours. The reaction was cooled down to room temperature, water (10 mL) was added, extracted with EtOAc (10 mL×2), second wash with Brine (10 mL). The organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 12 gram RediSep Rf™ silica gel cartridge eluting with 30% ethylacetate/hexanes to give the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[C:21]2[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=2[N:15]([CH3:23])[C:14](=[O:24])[C:13]=1[CH3:25].Cl[CH2:27][C@H:28]1[CH2:32][O:31]C(C)(C)[O:29]1>CN(C=O)C>[OH:29][C@H:28]([CH2:32][OH:31])[CH2:27][N:19]1[C:20](=[O:22])[C:21]2[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=3[F:3])=[C:13]([CH3:25])[C:14](=[O:24])[N:15]([CH3:23])[C:16]=2[N:17]=[CH:18]1
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: Cc1c(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H](O)CO)cnc2n(C)c1=O
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
Sodium hydride (67 mg, 3.5 mmol, 5 eq) was stirred in anhydrous DMF (500 μL) for 10 minutes. 5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (300 mg, 0.70 mmol, 1 eq, Example 12) in anhydrous DMF (300 μL) was added and the mixture stirred for 10 minutes. (R)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (180 μL, 1.32 mmol, 5 eq) was added and the mixture subjected to microwave irradiation at 135° C. for 1 hour. The solvent was removed in vacuo. The residue was taken up in H2O (1 mL) and THF (1 mL). 1N HCl (1 mL) was added and the solution stirred at RT for 1 hour. After evaporation in vacuo the residue was purified by HPLC to give 88 mg (25%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64 (s, 3 H) 2.11 (s, 3 H) 3.18 (d, J=5.31 Hz, 1 H) 3.32-3.42 (m, 1 H) 3.63-3.70 (m, 1 H) 3.70-3.82 (m, 1 H) 4.24-4.38 (m, 1 H) 4.78 (t, J=5.56 Hz, 1 H) 5.09 (d, J=5.56 Hz, 1 H) 6.62 (t, J=8.72 Hz, 1 H) 7.45 (dd, J=7.71, 2.15 Hz, 1 H) 7.66 (dd, J=10.61, 2.02 Hz, 1 H) 8.48 (s, 1 H) 10.16 (s, 1 H) [M+H] calc'd for C18H18FIN4O4, 501; found, 501.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([OH:31])([CH3:30])[CH3:29])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:32][C@H:33]1[CH2:38][NH:37][CH2:36][C@@H:35]([CH3:39])[NH:34]1>>[Cl:1][C:2]1[CH:27]=[C:26]([C:28]([OH:31])([CH3:29])[CH3:30])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:37]4[CH2:36][C@H:35]([CH3:39])[NH:34][C@H:33]([CH3:32])[CH2:38]4)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3Cl)c2)S1
Product: C[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4Cl)c3)S2)C[C@H](C)N1

Procedure:
5-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,5-(cis)-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-one and 2,6-(cis)-Dimethyl-piperazine following General Procedure C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH:18]([CH3:20])[CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:34])=[N:29]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH:18]([CH3:19])[CH3:20])[CH2:9][C:10]([C:13]([F:16])([F:14])[F:15])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:34])=[N:29]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)cccc2n1
Reactant: COc1c(F)cccc1C(CC(O)(C=O)C(F)(F)F)C(C)C
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1C(CC(O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F)C(C)C

Procedure:
In the same way as in Example 61, 280 mg (0.87 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-5-methyl-2-(trifluoromethyl)hexanal, 175 mg (1.1 mmol) of 5-amino-2-methylquinazoline and 0.45 ml of titanium tetraethoxide are reacted to give 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-5-methyl-2-(trifluoromethyl)hexan-2-ol. 360 mg of resulting crude imine are cyclized in the same way as in Example 61 at −30° C. with 6 ml (6 mmol) of 1 M boron tribromide solution in dichloromethane to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-70%) and subsequent preparative HPLC (SunFire C18, water/methanol) yield 6 mg of product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].N12CCN(CC1)CC2.[C:18]([O:22]CC)(=[O:21])[C:19]#[CH:20].CCCCCC>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9]/[CH:20]=[CH:19]/[C:18]([OH:22])=[O:21]
Reactant: C#CC(=O)OCC
Reactant: Cc1cccc(C)c1O
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cccc(C)c1O/C=C/C(=O)O

Procedure:
(E)-3-(2,6-dimethylphenoxy)acrylic acid 30a was prepared by the general method of Fan, et al. ((2006 Synthesis 2286): ethyl (E/Z)-3-(2,6-dimethylphenoxy)acrylate: 2,6-Dimethylphenol (1.5 g, 12.3 mmol) and 1,4-diazabicyclo[2.2.2]octane (100 mg, 0.9 mmol) and 2 mL of methylene chloride were combined with magnetic stirring. Ethyl propiolate (1.2 mL, 12.6 mmol) in 3 mL of methylene chloride was added drop wise over 5-10 minutes. Thin-layer chromatography of the reaction mixture (silica gel, hexane) showed the formation of two products. The reaction mixture was diluted with ˜70 mL of ethyl acetate and extracted with 10% potassium hydroxide, and then with saturated sodium chloride solution. The mixture was then extracted with 10% hydrochloric acid solution and then again with saturated sodium chloride solution. The ethyl acetate extract was dried with anhydrous magnesium sulfate, filtered, and evaporated to dryness to afford 2.9 g (100%) of product. A sample of this material (1.0 g) was purified by normal-phase chromatography (COMBIFLASH) to afford 650 mg of ethyl (E)-3-(2,6-dimethylphenoxy)acrylate [1H NMR (400 MHz, CDCl3): 1.24 (t, 3H, J=7.2 Hz), 2.17 (s, 6H), 4.13 (q, 2H, J=7.2 Hz), 5.00 (d, 1H, J=12.4 Hz), 7.04 (m, 3H), 7.74 (d, 1H, J=12.4 Hz], and 300 mg of the ethyl (Z)-3-(2,6-dimethylphenoxy)acrylate [1H NMR (400 MHz, CDCl3): 1.31 (t, 3H, J=7.2 Hz), 2.24 (s, 6H), 4.23 (q, 2H, J=7.2 Hz), 5.02 (d, 1H, J=6.8 Hz), 6.46 (d, 1H, J=6.8 Hz), 7.02 (m, 3H)]. (E)-3-(2,6-Dimethylphenoxy)acrylic acid 30a. Three hundred milligrams of ethyl (E)-3-(2,6-dimethylphenoxy)acrylate was combined with 0.5 g of KOH in 10 mL of a 20:80 mixture of water/ethanol and heated at reflux for 2.5 hours. The progress of the reaction was monitored by thin-layer chromatography (silica gel, hexane/ethyl acetate, 95:5). When the reaction had gone to completion, the reaction mixture was removed from heat and the ethanol was removed under reduced pressure. The reaction mixture was acidified with 5% hydrochloric acid solution and extracted with three 30-mL portions of ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The solid that formed was titrated with hexane and collected by vacuum filtration to afford 100 mg of (E)-3-(2,6-dimethylphenoxy)acrylic acid 30a. NMR (400 MHz, CDCl3): 2.17 (s, 6H), 5.00 (d, 1H, J=12.4 Hz), 7.05 (s, 3H), 7.80 (d, 1H, J=12.4 Hz), 11.0 (br s, 1H). MS (ESI): 215 [M+Na]+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[C:6]([O:10][C:11](=[O:20])[NH:12][CH2:13][C:14](=[O:19])N(OC)C)([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C>O1CCCC1>[C:6]([O:10][C:11](=[O:20])[NH:12][CH2:13][C:14]([CH:1]1[CH2:3][CH2:2]1)=[O:19])([CH3:7])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: Br[Mg]C1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)C1CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To 22 ml of a 0.5M solution of cyclopropylmagnesium bromide in tetrahydrofuran was added 2.2 g [(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester at −10° C. (acetone/ice) and the mixture was stirred at −10° C. for 30 min and then at ambient temperature for 30 min. (tic shows little conversion heptanes:ethyl acetate=1:1) To the resulting colorless solution was added another 22 ml of a 0.5M solution of cyclopropylmagnesium bromide in tetrahydrofuran and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched by addition of 10% citric acid. The phases were separated and the organic phase was purified by chromatography on silica gel with a gradient of heptane:ethyl acetate=9:1 to 1:1 to yield 1.300 g of the title compound as colorless oil. MS (EI): 199 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16][OH:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C([O-])(=O)C.[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39](I)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16][OH:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:39]2[CH:40]=[C:35]3[N:34]=[C:33]([CH2:32][CH2:31][C:27]4[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[CH:29][N:28]=4)[NH:42][C:36]3=[N:37][CH:38]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(c1ccc(Br)cc1)N(CCO)CCO
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N(CCO)CCO)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 59.7 %

Procedure:
A mixture of 0.486 g of N,N-bis-(2-hydroxyethyl)-4-bromobenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 6.5 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 15-8:1+1% NH4OH). Concentration of the chromatographically pure fractions and crystallisation from ethanol gives 0.29 g of the title compound as a solid of m.p. 127-128° C. The mass spectrum shows the molecular peak MH+ at 498.3 Da.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[CH2:28]([O:30][C:31](=[O:38])COS(C)(=O)=O)C>>[C:31]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:25][CH3:26])[C:4]([OH:3])=[O:27])=[CH:12][CH:11]=2)=[CH:23][CH:22]=1)([O:30][CH3:28])=[O:38]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(O)cc2)cc1)OC
Reactant: CCOC(=O)COS(C)(=O)=O
Product: COC(=O)c1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 263, Step B) and methane-sulfonyloxy-acetic acid ethyl ester (Step A) by following the procedure described for Example 264. 1H-NMR (MeOD, 200.15 MHz): δ 7.13 (d, 2H, J=8.6), 6.86–6.81 (m, 6H), 4.57 (s, 2H), 4.15–4.06 (m, 4H), 3.91 (dd, 1H, J=7.8, 4.8), 3.31 (s, 3H), 2.99 (dd, 1H, J=14.2, 4.6), 2.85 (dd, 1H, J=14.2, 7.5), 2.17 (qn, 2H, J=6.2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].Cl.[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[CH3:29].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:34])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: CCOC(=O)CN
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg), glycine ethyl ester hydrochloride (135 mg) and triethylamine (450 mg) were added to pyridine (1,000 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted 4 times repeatedly. Ethanol (1 ml) and distilled water (1 ml) were added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain an about 1:1 mixture (106 mg) of the title compound and 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which is the raw material, as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2ccc(Cl)cn2)cc1
Yield: 93 %

Procedure:
Palladium(0),tetrakis(triphenylphosphine) (4.69 g, 4.05 mmol) was added to a stirred suspension of 2,5-dichloropyridine (12.0 g, 81.08 mmol), 4-hydroxybenzene boronic acid (11.2 g, 81.1 mmol) and potassium carbonate (11.2 g, 81.1 mmol) in dioxane (100 mL) and water (100 mL). The mixture was refluxed for 2 hours, then partitioned between diethyl ether (100 mL) and water (100 mL). The organics were washed with brine (100 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 4% methanol in dichloromethane, to afford the title compound as an off-white solid (15.5 g, 81%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)=O)[N:10]=2)[CH2:4][C:3]1([CH3:21])[CH3:20].[F:22][C:23]([F:35])([CH3:34])[CH2:24][O:25][C:26]1[C:31]([CH2:32][NH2:33])=[CH:30][N:29]=[CH:28][N:27]=1>O1CCOCC1>[F:35][C:23]([F:22])([CH3:34])[CH2:24][O:25][C:26]1[C:31]([CH2:32][NH:33][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:21])([CH3:20])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:30][N:29]=[CH:28][N:27]=1
Reactant: CS(=O)c1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Reactant: CC(F)(F)COc1ncncc1CN
Solvent: C1COCCO1
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Yield: 69.6 %

Procedure:
A solution of 4-(((1S,4R)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile (1.0 equiv) and (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (1.5 equiv) in dioxane (0.15 M) was heated at 110° C. for 1 h. Standard work-up provided 2-(((4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methyl)amino)-4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)pyrimidine-5-carbonitrile (69.6% yield). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.72 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.99 (t, J=5.66 Hz, 1H), 7.17 (d, J=7.81 Hz, 1H), 4.64 (t, J=12.89 Hz, 2H), 4.39-4.49 (m, 2H), 4.29 (d, J=3.51 Hz, 1H), 3.85-4.00 (m, 1H), 3.12 (br. s., 1H), 1.73 (t, J=19.14 Hz, 4H), 1.42-1.55 (m, 3H), 1.21-1.33 (m, 3H), 1.10 (br. s., 1H), 0.59-0.78 (m, 5H). MS (ESI) m/z 448.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].Br[C:41]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:42]=1[C:43]#[N:44].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C(Cl)Cl.CN(C=O)C>[C:43]([C:42]1[CH:45]=[C:46]([C:49]([F:50])([F:51])[F:52])[CH:47]=[CH:48][C:41]=1[C:14]1[C:13]2[C:17](=[CH:18][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=3[O:2][CH3:1])[C:29]3[S:33][N:32]=[CH:31][N:30]=3)(=[O:8])=[O:9])=[CH:11][CH:12]=2)[N:16]([CH3:19])[CH:15]=1)#[N:44]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c3c2)c(OC)c1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C#N)cn(C)c3c2)c(OC)c1
Temperature: 85 °C

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.075 g, 0.131 mmol), 2-bromo-5-(trifluoromethyl)benzonitrile (0.082 g, 0.329 mmol). potassium phosphate (0.098 g, 0.460 mmol), and PdCl2(dppf)-CH2Cl2 (10.74 mg, 0.013 mmol). DMF (0.876 ml) was added, and the vial was flushed with Ar, sealed, and heated to 85° C. for two hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. The material was purified via column chromatography (0 to 100% EtOAc/Heptane) to give 3-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as a light yellow solid. The solid was dissolved in DCM (0.5 ml) and TFA (0.5 ml, 6.49 mmol), and the resulting mixture was stirred for 15 min. The mixture was concentrated in vacuo. The residue was dissolved in acetonitrile, and passed through a PEAX ion exchange column. The column was flushed several times with acetonitrile, then the product was liberated by flushing several times with an 1M HCl solution in 15% MeOH/EtOAc. The solution was concentrated to afford 3-(2-cyano-4-(trifluoromethyl)phenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.022 g, 0.047 mmol, 36.1% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ=8.44 (s, 1 H), 8.42 (s, 1 H), 8.17 (s, 1 H), 8.14-8.10 (m, 1 H), 8.07 (d, J=1.2 Hz, 1 H), 7.95 (d, J=8.1 Hz, 1 H), 7.83 (d, J=8.5 Hz, 1 H), 7.60 (dd, J=1.6, 8.5 Hz, 1 H), 4.01 (s, 3 H). m/z (ESI) 464.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][C:6](=[O:12])[NH:7]2.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][C:6](=[O:12])[NH:7]2
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c(=O)c2c(Cl)cccc2[nH]1
Agent: O=S(=O)(O)O
Product: O=c1[nH]c(=O)c2c(Cl)c([N+](=O)[O-])ccc2[nH]1
Reaction time: 1 h

Procedure:
A solution of the above quinazolinedione (0.98 g, 5.0 mmol) in conc. H2SO4 (5 mL) was cooled to −10° C., and 90% HNO3 (0.35 g, 5.0 mmol) was added with stirring. Stirring continued for 1 h at −10° C., and 1.5 h at room temperature. The mixture was poured onto ice, filtered, washed with water and dried to give 5-chloro-6-nitroquinazolin-2,4-dione, along with some of the 8-nitro isomer (1.3 g, 94%).