Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CO>[F:10][C:11]1[N:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: N#Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1ccc(-c2ccc(F)nc2)cc1
Temperature: 110 °C
Yield: 78 %

Procedure:
A mixture of 4-bromobenzonitrile (0.20 g, 1.1 mmol), (6-fluoropyridin-3-yl)boronic acid (0.15 g, 1.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (1:1) complex (0.04 g, 0.05 mmol) and potassium carbonate (0.46 g, 3.3 mmol) in 1,4-dioxane (7 mL), and water (3 mL) was heated at 110° C. for 2 h. After cooled to r.t., the mixture was diluted with MeOH, filtered, concentrated under reduced pressure and purified by flash chromatography on a silica gel column eluting with 5% MeOH in DCM to afford the desired product (0.17 g, yield: 78%). Analytic LCMS (M+H)+: m/z=199.2.
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=O)[CH2:7][S:8][C@H:3]12.[C:16]1([CH:22]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Reactant: C(c1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: NC1C(=O)N2C(C(=O)O)=C(C=Cc3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 0.3 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in 3 ml of THF is treated at room temperature with 1.4 ml of BSA. The reaction mixture is stirred at room temperature for 10 minutes. A clear solution is obtained containing N,O-bistrimethylsilyl-7-amino-3-formyl-3-cephem-4-carboxylic acid. The solution is cooled to 0° and treated with a solution of 0.53 g of phenylmethylene triphenylphosphorane in 4 ml of THF. After 24 hours stirring at 0° the reaction mixture is worked up as described in example 23). A mixture of the isomers (6 parts Z-isomer and 11 parts E-isomer) is obtained.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH2:23][C:24]4[CH:28]=[CH:27][O:26][C:25]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH2:23][C:24]4[CH:28]=[CH:27][O:26][C:25]=4[C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1ccoc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2occc2C1
Temperature: 70 °C
Reaction time: 6 h
Yield: 8 %

Procedure:
To a solution of methyl 13-cyclohexyl-5-[2-(dimethylamino)ethyl]-4,5,6,7-tetrahydrofuro[3′,2′:6,7][1,4]diazocino[1,8-a]indole-10-carboxylate in MeOH (0.07 M), 15 eq 1N NaOH was added. The solution was stirred at 70° C. for 6 h. The reaction was acidified to pH 2 with HCl and the solvent was evaporated in vacuo. The crude was then purified by prep RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×150 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a brown powder in 8% yield (over two steps).
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[F:29][C:30]1[CH:54]=[CH:53][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:41]3[S:42][C:43]([C:47]([O:49]CC)=[O:48])=[C:44]([CH3:46])[N:45]=3)[C:36]2=[O:52])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:41]3[S:42][C:43]([C:47]([OH:49])=[O:48])=[C:44]([CH3:46])[N:45]=3)[C:36]2=[O:52])=[CH:53][CH:54]=1
Reactant: CCOC(=O)c1sc(N2CCCN(Cc3ccc(F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Yield: 96 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 2-(3-(4-fluorobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 96% yield: MS (ES+) m/z 350.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([F:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>[Pd].C(O)C>[NH2:12][C:11]1[C:2]([F:1])=[C:3]([C:8]([F:15])=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1c(F)ccc(N)c1F
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a 1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under an atmosphere of N2. Ethanol (350 mL, 0.25M) was added, and then H2 was passed through the reaction mixture for 15 minutes. The reaction mixture was then left to stir under two H2 balloons overnight. The following day, the reaction mixture was re-flushed with fresh H2 balloons and stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter (“GF/F”) paper twice. The volatiles were removed to afford methyl 3-amino-2,6-difluorobenzoate as an oil (15.66 g, 99%). The material was taken directly onto the next step.
Reaction SMILES: O[CH2:2][CH:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=[O:5].P(=O)(O)O>>[CH3:9][CH:8]([CH3:10])[CH2:7][C:3](=[CH2:2])[C:4]([OH:6])=[O:5]
Reactant: CC(C)CC(CO)C(=O)O
Agent: O=[PH](O)O
Product: C=C(CC(C)C)C(=O)O

Procedure:
The compounds of formula I can be prepared using as a starting material 2-(hydroxymethyl)-4-methylpentanoic acid. Heating the starting material with phosphonic acid yields 4-methyl-2-methylenepentanoic acid which can in turn be reacted with a thio acid having the formula
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10](=[O:19])[C:9]=2[CH:20]=1.[OH-].[Na+]>C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[CH:10]([OH:19])[C:9]=2[CH:20]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccccc1CC2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)C(O)c1ccccc1CC2

Procedure:
In a manner similar to that described in the preceding examples, 0.5 gram (13 millimoles) of sodium borohydride was added to a solution of 1 gram (43 millimoles) of 10,11-dihydro-3-methoxy-5H-dibenzo[a,d]cyclohepten-5-one in 20 milliliters of ethanol with an added drop of 40 percent sodium hydroxide solution and the mixture heated overnight to obtain 10,11-dihydro-3-methoxy-5H-dibenzo[a,d]cyclohepten-5-ol (5-hydroxy intermediate compound) in the reaction mixture.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][S:42](Cl)(=[O:44])=[O:43])=[CH:37][CH:36]=1)([O-:34])=[O:33]>N1C=CC=CC=1.CCOC(C)=O>[Cl:16][C:9]1[CH:10]=[N+:11]([O-:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[CH2:7][C@@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[O:5][C:3](=[O:4])[CH2:2][NH:1][S:42]([CH2:41][C:38]1[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=1)(=[O:43])=[O:44]
Reactant: NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-4-(2-(2-aminoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (prepared in an analogous manner to that described in Scheme 1, Step 1-2) (243 mg, 0.509 mmol) dissolved in pyridine (1 mL), cooled at 0° C., (4-nitrophenyl)methanesulfonyl chloride (100 mg, 0.424 mmol) was added. The mixture was stirred at 0° C. for 2 hours. The mixture was then diluted with EtOAc and washed with HCl 0.1N, NaHCO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and the solvent was evaporated. (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-((4-nitrophenyl)methyl-sulfonamido)acetoxy)ethyl)pyridine 1-oxide was obtained (287 mg, 0.42 mmol, quantitative yield).
Reaction SMILES: C1(N2C3N=CN=C(N)C=3[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[N:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)=C2)CCC1.Br[C:32]1[N:33]=[C:34]([CH:42]2[CH2:45][CH2:44][CH2:43]2)[N:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=12>>[CH:42]1([C:34]2[N:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]3=[C:32]([C:15]3[CH:7]=[C:19]4[C:18]([C:17]([CH3:16])=[N:22][C:21]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:23][CH:24]=3)[N:33]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: Nc1ncnc2c1c(-c1ccc3cnc(-c4ccccc4)nc3c1)cn2C1CCC1
Reactant: Nc1nccn2c(C3CCC3)nc(Br)c12
Product: Cc1nc(-c2ccccc2)nc2cc(-c3nc(C4CCC4)n4ccnc(N)c34)ccc12

Procedure:
Synthesized as 7-cyclobutyl-5-(2-phenylquinazolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine from of 1-bromo-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine (16 mg, 0.06 mmol). Crude material was purified by preparative TLC (silica gel, 5% MeOH in DCM) followed by a recrystallization (EtOAc) and trituration (hexanes) to afford the title compound as a light yellow solid; MS (ES+): m/z 407.1 (100); HPLC: tR (min) 2.44 (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15]O)=[CH:9]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42].[H-].[Na+]>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3ccc(CCCO)c3)c(F)c2)C(=O)O1
Reactant: CS(N)(=O)=O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3ccc(CCCNS(C)(=O)=O)c3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
A solution of 100 mg (0.266 mmol) of the compound of Example 25 (previously dried at 60° C. under 0.1 mmHg for 18 h prior to use) and 88 mg (120 μL, 0.88 mmol) of triethylamine in 2 mL dichloromethane at 0° C. was treated with 85 mg (58 μL, 0.73 mmol) of methanesulfonyl chloride, followed by stirring at 0° C. for 30 min. The solution was diluted with dichloromethane and extracted with water (2×) and saturated sodium bicarbonate solution. Drying (Na2SO4) and concentration in vacuo afforded a solid which was dissolved in 2 mL DMF and treated via cannula to a 0° C. solution of 38 mg (0.40 mmol) of methanesulfonamide in 2 mL DMF which had been previously treated with 10 mg (17 mg of 60% in oil, 0.43 mmol) of sodium hydride. The solution was then warmed at 60° C. for 18 h. The solution was cooled and the DMF removed in vacuo, and the residue was dissolved in ethyl acetate and extracted with water (2×). Drying (Na2SO4) and concentration in vacuo afforded a solid which was subjected to radial chromatography on a 2 mm chromatotron plate, eluting with 1-4% (v/v) methanol in dichloromethane. These procedures afforded 31 mg (26%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.61, 7.56, 7.35, 7.23, 6.92, 6.81, 6.19, 6.06, 4.81, 4.29, 4.07, 3.82, 3.67, 3.22, 2.95, 2.62, 2.04, 1.90. ##STR5##
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>[O-2].[Mn+2]>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:1]
Reactant: N#Cc1cnc2ccc(CO)cc2c1-c1cccnc1
Agent: [Mn+2]
Agent: [O-2]
Product: N#Cc1cnc2ccc(C=O)cc2c1-c1cccnc1

Procedure:
Similar procedure as described in example 61i was used, starting from 6-hydroxymethyl-4-pyridin-3-yl-quinoline-3-carbonitrile (example 63b), and activated manganese oxide to give 6-formyl-4-pyridin-3-yl-quinoline-3-carbonitrile. LC-MS m/e 260 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[CH2:2][NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CN)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
0.40 g of ethyl 2-[3-(aminomethyl)-4-methoxybenzyl]butanoate and 0.29 g of 4-(trifluoromethyl)benzoic acid were dissolved in 5 ml N,N-dimethylformamide, and 0.24 ml diethyl cyanophosphonate and 0.21 ml triethylamine were added under ice-cooling. After stirring the reaction mixture at room temperature for 16 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 0.59 g of ethyl 2-[4-methoxy-3-({[4-(trifluoromethyl)benzoyl]amino}methyl)benzyl]butanoate was obtained.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.Br.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:10]([N:17]1[CH2:18][CH2:19][N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Agent: Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 89 %

Procedure:
80 g (0.31 mol) of ethyl 2,3-dibromopropionate diluted in 300 ml of benzene are added dropwise, but fairly rapidly, to a warm solution of 72 g (0.3 mol) of N,N'-dibenzylethylenediamine, 700 ml of benzene and 50 ml (0.36 mol) of triethylamine. After the addition, reflux is maintained for 3 hours (triethylamine hydrobromide precipitates in the reaction mixture). The mixture is cooled and filtered through fritted glass, and the solid is washed with ether. The flitrate is washed with 200 ml of saturated sodium hydrogen carbonate solution and then twice with 100 ml of water. The organic phases are dried over magnesium sulfate and the solvents are evaporated off in vacuo. Approximately 100 ml of toluene are added, and evaporation is continued. The resulting residue is diluted in 400 ml of absolute ethanol and saturated with gaseous hydrogen chloride. The salt precipitates by the addition of ether. Filtering, washing with ether and drying yield from 100 to 110 g of white crystals.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[C:5]([F:11])([F:10])[S:6]([O-:9])(=[O:8])=[O:7].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.[F:38][C:39]([F:54])([S:50](Cl)(=[O:52])=[O:51])[C:40]([F:49])([F:48])[CH:41]1[CH2:46][CH:45]2[CH2:47][CH:42]1[CH2:43][CH2:44]2.C(N(CC)CC)C.O>ClCCl>[F:17][C:2]([F:1])([F:16])[C:3]([F:14])([F:15])[C:4]([F:12])([F:13])[C:5]([F:10])([F:11])[S:6]([O-:9])(=[O:8])=[O:7].[F:54][C:39]([F:38])([S:50]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:52])=[O:51])[C:40]([F:48])([F:49])[CH:41]1[CH2:46][CH:45]2[CH2:47][CH:42]1[CH2:43][CH2:44]2
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)C1CC2CCC1C2
Reactant: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1)C(F)(F)C(F)(F)C1CC2CCC1C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.2 %

Procedure:
30 g of 4-hydroxyphenyl diphenylsulfonium nonafluoro-n-butanesulfonate was dissolved in 300 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 30.6 g of 1,1,2,2-tetrafluoro-2-(norbornan-2-yl)ethanesulfonyl chloride and 10.5 g of triethylamine were added in this order. The mixture was stirred for 20 minutes at room temperature. After the addition of 100 g of ion-exchanged water, the mixture was transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the solution was shaken and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried using anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dichloromethane solution, the residual liquid was dried under reduced pressure to obtain 23.5 g of 4-[1,1,2,2-tetrafluoro-2-(norbornan-2-yl)ethanesulfonyloxy]phenyl diphenylsulfonium nonafluoro-n-butanesulfonate. This compound is indicated as “acid generator (A-3)”.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([OH:13])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[C:16]([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([N:8]1[CH:12]=[C:11]([O:13][CH3:16])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cnn(Cc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 1-benzyl-1H-pyrazol-4-ol (compound 244.2, 1.40 g, 8.04 mmol) in N,N-dimethylformamide (20 mL). Iodomethane (703 μL, 11.3 mmol) and Cs2CO3 (3.68 g, 11.3 mmol,) were added and the resulting mixture was stirred for 3 h at room temperature. The mixture was concentrated under reduced pressure, then diluted with EtOAc (200 mL). The mixture was washed with brine (3×80 mL), and the organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound as a yellow oil (1.30 g, 86%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[C:10]=2[N:11]=1.[Cl:21][C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])(=[O:31])=[O:30])=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:21][C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])(=[O:31])=[O:30])=[CH:26][C:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]4[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=4)[C:10]=3[N:11]=2)=[CH:24][N:23]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: COc1ccc(Nc2ncnc3ccc(Cl)nc23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)cn1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
A mixture of 6-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (Intermediate 22) (0.040 g, 0.139 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.066 g, 0.153 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.011 g, 0.014 mmol) and 1 N aq. sodium bicarbonate (0.278 ml, 0.278 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(6-methoxypyridin-3-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.024 g, 31%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 3.89 (3H, s), 6.94 (3H, s), 6.89-7.05 (1H, d, J=8.4 Hz), 7.17-7.28 (1H, m), 7.50-7.65 (1H, m), 7.74-7.86 (1H, m), 8.17 (1H, dd, J=2.4, 8.8 Hz), 8.33 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.57 (1H, d, J=8.8 Hz), 8.62 (2H, s), 8.82 (1H, s), 9.48 (1H, s), 10.33 (1H, s), 10.98 (1H, br s). m/z=556.2 [M+1]+.
Reaction SMILES: [I:1]I.[Br:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12]>S([O-])([O-])(=O)=O.[Ag+2].C(O)C>[Br:3][C:4]1[C:5]([C:11]([F:12])([F:13])[F:14])=[CH:6][C:7]([NH2:8])=[C:9]([I:1])[CH:10]=1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(Br)cc1I
Temperature: 25 °C

Procedure:
Iodine (1.4 g, 5.5 mmol, 1.1 eq.) was gradually added to a mixture solution of 4-bromo-3-trifluoromethyl aniline (1.2 g, 1.0 mmol), silver sulfate (1.72 g, 5.5 mmol, 1.1 eq.), and anhydrous ethanol (35 ml). This was stirred at room temperature for two and half hours. The reaction mixture was filtered through Celite, and washed with ethyl acetate. The wash solution was washed with aqueous solutions of 10% sodium thiosulfate, saturated sodium bicarbonate, and saturated sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Crude solid 4-bromo-2-iodo-5-trifluoromethyl-phenylamine was obtained by concentration under reduced pressure. The resulting crude product was used in subsequent reactions without being purified.