Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([N:6]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.C1CCCCC1.[Br:27]Br>O1CCCC1>[Br:27][C:10]1[N:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[N:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=1
Reactant: BrBr
Reactant: CN(C)S(=O)(=O)n1ccc(C(F)(F)F)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CN(C)S(=O)(=O)n1nc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide (i.e. the product of Example 10, Step A) (4.25 g, 17.5 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C., and then 2 M n-butyllithium in cyclohexane (10.0 mL, 20.0 mmol) was added dropwise. The reaction mixture was stirred a further 30 minutes, and then bromine (1.0 mL, 3.1 g, 18.7 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes, warmed to room temperature, and quenched with brine (50 mL). The resulting solution was extracted with diethyl ether, dried (MgSO4), and concentrated under reduced pressure to give 6.77 g of title compound as a light yellow oil. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][C:5]([I:8])=[N:6][CH:7]=1.[S-:10][C:11]#[N:12].[K+]>C(O)=O>[Cl:1][C:2]1[C:3]([S:10][C:11]#[N:12])=[N:4][C:5]([I:8])=[N:6][CH:7]=1
Reactant: N#C[S-]
Reactant: Clc1cnc(I)nc1I
Agent: [K+]
Solvent: O=CO
Product: N#CSc1nc(I)ncc1Cl
Yield: 62.5 %

Procedure:
In 100 ml of formic acid, a reaction of 18.4 g of 5-chloro-2,4-diiodopyrimidine and 6.0 g of potassium thiocyanate was conducted at 60° C. for 1 hour in a similar manner as Synthesis Example 1. Then, the reaction mixture was treated in a similar procedure as Synthesis Example 1, there was obtained a 62.5% yield of 5-chloro-2-iodo-4-thiocyanopyrimidine, m.p. 183°-186° C.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[N:19]1([C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: c1ccc(CN2CCOc3nc(N4CCOCC4)cnc3C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1nc2c(nc1N1CCOCC1)OCCNC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
A mixture of 8-benzyl-3-(morpholin-4-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (259 mg), 20% Pd(OH)2/C (300 mg) and methanol (2 mL) was stirred under a hydrogen atmosphere at 50° C. for 2 hr. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 0→10% methanol/ethyl acetate) and recrystallized (ethyl acetate-hexane) to give the title compound (54.1 mg, 29%) as colorless crystals.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:29]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=1)#[N:30]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cc(C)cc3C)cc2c1O
Reactant: NCC(=O)O
Product: Cc1cc(C)c(Oc2ccc3c(C#N)nc(C(=O)NCC(=O)O)c(O)c3c2)c(C)c1

Procedure:
The title compound was synthesized from 1-cyano-4-hydroxy-6-(2,4,6-trimethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=404.4.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([N+:22]([O-])=O)=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[NH2:22][C:11]1[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[CH:21][CH:20]=[CH:19][C:12]=1[C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14]
Reactant: CON(C)C(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)c1N
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A mixture of Intermediate 37D (1.25 g, 3.53 mmol) and 10% Pd/C (200 mg, 0.188 mmol) in EtOAc (50 mL) was purged with hydrogen. The mixture was then stirred under a hydrogen atmosphere for 1.5 h. The suspension was filtered, and the filtrate was concentrated to dryness. The crude material was purified by flash chromatography (SiO2, 24 g column, EtOAc/hexane=0-40%) to afford Intermediate 37E (939 mg, 82%). HPLC: RT=2.986 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=325.2 [M+H+]; 1H NMR (400 MHz, chloroform-d) δ 7.32 (dd, J=7.7, 1.5 Hz, 1H), 7.11 (dd, J=7.5, 1.5 Hz, 1H), 6.68-6.62 (m, 1H), 5.21 (br. s., 2H), 4.71 (s, 2H), 3.61 (s, 3H), 3.36 (s, 3H), 0.92 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.O[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH3:31][C:28]1[CH:29]=[CH:30][C:25]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]3)=[CH:22][CH:23]=2)=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO)cc2)CC1
Reactant: Cc1ccc(O)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(OCCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1
Temperature: 55 °C

Procedure:
tert-Butyl 4-[4-(2-hydroxyethyl)benzyl]piperazine-1-carboxylate (1.44 g), 2-hydroxy-5-methylpyridine (0.737 g), tri-n-butylphosphine (1.76 mL), 1,1′-(azodicarbonyl)-dipiperidine (1.70 g), and THF (16.5 mL) were mixed in a 20 mL process vial. The vial was sealed, and the reaction mixture was heated with microwaves to 55 ° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt =10/1 to 3/10) to give tert-butyl 4-(4-{2-[(5-methylpyridin-2-yl)oxy]ethyl}benzyl)piperazine-1-carboxylate as a pale yellow amorphous (1.01 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1.[CH:16]1([C:19]2[NH:23][N:22]=[C:21]([NH2:24])[CH:20]=2)[CH2:18][CH2:17]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:24][C:21]2[CH:20]=[C:19]([CH:16]3[CH2:18][CH2:17]3)[NH:23][N:22]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1
Reactant: Clc1cc(-c2ccccc2Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCO
Product: Clc1nc(Nc2cc(C3CC3)[nH]n2)cc(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 38.7 %

Procedure:
2,4-Dichloro-6-(2-chloro-phenyl)-pyrimidine (180 mg, 0.694 mmol) and 5-cyclopropyl-1H-pyrazol-3-ylamine (128 mg, 1.04 mmol) was taken into 3 ml of ethanol. The reaction was stirred at room temperature for 4 days. The reaction was evaporated in vacuo and the crude product purified by flash chromatography (SiO2) eluting with ethyl acetate/hexane (1:1) to afford 93 mg of the desired product. HPLC (C18 column) Rt 6.23 mins.; MS m/z 346.1 (M+H) 344.1 (M−H)
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH3:39])[C:30]=2[C:34]([F:37])([F:36])[F:35])[C:25]=1[C:40](=[S:47])[N:41]([CH3:46])[CH2:42][C:43](O)=[O:44].N>CN(C=O)C.O1CCCC1>[F:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH3:39])[C:30]=2[C:34]([F:36])([F:37])[F:35])[C:25]=1[C:40]([N:41]([CH2:42][C:43]([NH2:2])=[O:44])[CH3:46])=[S:47]
Reactant: COc1ccc2c(C(=S)N(C)CC(=O)O)c(F)ccc2c1C(F)(F)F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=S)N(C)CC(N)=O)c(F)ccc2c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
1-Hydroxybenzotriazole (0.84 g, 1.5 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 1.2 eq) were added to a stirred solution of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine (1.50 g, 4.15 mmol) in anhydrous DMF (15 mL) at room temperature under a dry nitrogen atmosphere. After 13/4 hours, a saturated solution of ammonia in tetrahydrofuran (100 mL) was added to the reaction mixture at room temperature. After 1 hour, the reaction was cooled to 0° C. and ammonia gas was bubbled directly into the reaction mixture for 15 minutes. While still cool, the reaction mixture was filtered and the solid was washed with THF (2×10 mL). The solvent was removed from the filtrate and the residue was diluted with water (500 mL). The aqueous phase was extracted with ether (6×100 mL). The extracts were combined and preabsorbed onto silica gel. The absorbate was flash chromatographed (19:1 chloroform:methanol, silica) and the resulting product was re-flash chromatographed (chloroform to 49:1 chloroform:methanol, silica) to provide the title compound as a light yellow solid (0.30 g, 20%), m.p. 222°-224° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4].[OH-].[Na+].[S:10](=O)([OH:12])[O-:11].[Na+]>>[CH3:7][CH:6]1[CH:2]([CH3:1])[C:3](=[O:5])[O:4][S:10]1(=[O:12])=[O:11]
Reactant: C/C=C(\C)C(=O)O
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CC1C(=O)OS(=O)(=O)C1C

Procedure:
100 g. of α-methyl-crotonic acid is reacted with sodium hydroxide to neutralize the carboxyl group. Sodium bisulfite (104 g.) in aqueous solution is added and the reaction continued as described in earlier examples to obtain 3,4-dimethyl-1,2-oxathiolane-5-one-2,2-dioxide
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[S:21](N)([NH2:24])(=[O:23])=[O:22].[H-].[H-].[H-].[H-].[Li+].[Al+3]>N1C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:21](=[O:23])(=[O:22])[NH:24]2)=[CH:15][CH:16]=1
Reactant: NS(N)(=O)=O
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc2cccnc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=S1(=O)Nc2c(ccc3cccnc23)C(c2ccc(F)cc2)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.6 %

Procedure:
(8-Amino-quinolin-7-yl)-(4-fluoro-phenyl)-methanone 367 (100 mg, 0.38 mmol) and sulfamide (361 mg, 3.76 mmol) in pyridine (3 ml) and were heated in a microwave at 140° C. for 2 h. After cooling, the mixture was concentrated in vacuo. The residue was dissolved in anhydrous THF (5 ml). LiAlH4 (26 mg, 0.75 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (5 ml) and the resulting precipitate was collected by filtration and dried. The crude solid was purified by preparative HPLC (acidic conditions 1) to give the title compound (27 mg, 22%).
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[Na+].[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[N:11]=[C:10]([C:24]#[N:25])[CH:9]=1.O>CO>[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[Cl:23])[N:11]=[C:10]([C:24]#[N:25])[C:9]=1[S:3][C:4]#[N:5]
Reactant: N#Cc1cc(N)n(-c2ccc(C(F)(F)F)cc2Cl)n1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CSc1c(C#N)nn(-c2ccc(C(F)(F)F)cc2Cl)c1N
Temperature: 20 °C
Yield: 91.2 %

Procedure:
Bromine (0.5 ml) was added over 10 minutes to a stirred solution of sodium thiocyanate (1.7 g) in anhydrous methanol at −65° C. A solution of 5-amino-1-(2-chloro-4-(trifluoromethyl)phenyl]-1-H-pyrazole-3-carbonitrile (1.5 g) in anhydrous methanol was added over 10-minutes and the stirred mixture allowed to warm to 20° C. over 16-hours. After pouring into water the precipitate was collected and dried to give 5-amino-1-[2-chloro-4-(trifluoromethyl)phenyl]-4-thiocyanato-1H-pyrazole-3-carbonitrile (1.64 g). HPLC (C-18 column, eluting with 3:1 CH3CN/H2O at 1.0 ml/min.) showed the compound as a peak of 86.6% area at 5.11 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[CH2:17](Br)[CH3:18].[H-].[Na+].CC(C)([O-])C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:6]([N:7]([CH2:17][CH3:18])[C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CCBr
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl

Procedure:
In step 2d, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (2-8) is alkylated with ethyl bromide (EtBr) in the presence of a base, such as sodium hydride (NaH) or sodium tert-butoxide (NaOt-Bu), in a polar aprotic solvent, such as tetrahydrofuran, at temperatures from about 20° C. to about 40° C., over a period of time of about 60 hours to about 168 hours, to yield N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (2-9). It has been discovered that use of an iodide additive, such as potassium iodide (KI) or tetrabutylammonium iodide (TBAI) can decrease the time necessary for the reaction to occur to about 24 hours. It has also been discovered that heating the reaction at about 50° C. to about 70° C. in a sealed reactor (to prevent loss of ethyl bromide) also decreases the reaction time to about 24 hours.
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)=[CH:19][C:18]=1O.N1C=CC=CC=1>C(Cl)Cl>[F:6][C:5]([F:8])([F:7])[S:2]([O:1][C:18]1[CH:19]=[C:20]([C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)[CH:21]=[CH:22][C:17]=1[CH3:16])(=[O:4])=[O:3]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(C2(C)COC2)cc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C2(C)COC2)cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Tf2O (3.07 mL, 18.2 mmol) was added dropwise to a solution of 2-methyl-5-(3-methyloxetan-3-yl)phenol (2.70 g, 15.2 mmol) and pyridine (1.71 mL, 21.2 mmol) in DCM (25 mL) at 0° C. The red/orange mixture was stirred at 0° C. for 1.5 h, then partitioned between DCM and water. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/heptane) to provide 2-methyl-5-(3-methyloxetan-3-yl)phenyl trifluoromethanesulfonate. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.38 (d, J=8.08 Hz, 1 H) 7.26 (dd, J=7.96, 1.89 Hz, 1 H) 7.14 (d, J=1.77 Hz, 1 H) 4.89 (d, J=5.56 Hz, 2 H) 4.66 (d, J=5.81 Hz, 2 H) 2.41 (s, 3 H) 1.75 (s, 3 H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([NH2:20])=[N:18][N:19]=2)[N:16]=1>>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([NH2:20])=[N:18][N:19]=2)[N:16]=1
Reactant: Nc1nnc2ccc(Cl)nn12
Reactant: OCC(F)(F)F
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Nc1nnc2ccc(OCC(F)(F)F)nn12

Procedure:
2,2,2-Trifluoroethanol (1 ml), sodium hydride (86 mg) and 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001, 100 mg) were reacted according to W1.004. 87 mg of the title compound were obtained in solid form.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](I)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd]Cl.O.CCOC(C)=O.CN(C=O)C>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=3)=[O:28])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:19]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3Cl)c3ccccc32)cc1
Yield: 59.7 %

Procedure:
Add N-(4-Fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide (268 mg, 0.0.50 mmol), 2-chlorophenylboronic acid (78.2 mg, 0.50 mmol), PdCl2 (dppf).CH2Cl2 (41 mg, 0.05 mmol) and 2M Na2CO3 (0.55 mL, 1.1 mmol) respectively to DMF (15.0 mL) at ambient temperature under N2. Heat the reaction to 100° C. for 16 h. Cool the reaction to ambient temperature and pour into a H2O-EtOAc mixture (200 mL/100 mL). Separate the EtOAc, extract several times with H2O and wash with brine. Dry (MgSO4), filter and evaporate the filtrate. Purify the crude material on silica gel using a gradient hexane-EtOAc system to give 0.155 g (60% yield) of 4-[3-(2-chloro-phenyl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide: Mass spectrum (m/e)M−1) 517.0787.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5]1)(=O)[NH2:2].ClC1N=C(Cl)N=C(Cl)N=1>CN(C=O)C.[Au]>[C:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:5]1)#[N:2]
Reactant: NC(=O)[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Au]
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of benzyl N-[(1S,3R)-3-carbamoylcyclohexyl]carbamate, 18d, (0.69 g, 2.50 mmol) in DMF (10 mL) at 0° C. was treated with 2,4,6-trichloro-1,3,5-triazine (0.61 g, 3.29 mmol) and allowed to stir while slowly warming to room temperature. After 20 minutes, the solution became gold in color. After 1 hour a precipitate had formed. Stirred for an additional 3 hours then quenched with ice water (100 mL) and extracted with CH2Cl2 (2×125 mL) then washed with 1N HCl (100 mL). The organic layer was concentrated in vacuo to afford an 730 mg of a residue that was purified using a pad of silica gel (45 mL) using 30% EtOAc/hexanes as eluent to afford 621 mg of a white solid after vacuum drying.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24]C3C=CC=CC=3)=[O:23])=[CH:17][CH:16]=2)[N:4]=1.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]O)=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:1][N:2]([CH3:31])[C:3]1[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=3)=[O:23])=[CH:17][CH:16]=2)[N:4]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(NC(=O)Oc3ccccc3)cc2)nc1N(C)C
Reactant: OCc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)OCc3ccc(F)cc3)cc2)nc1N(C)C
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A mixture of methyl (4-(dimethylamino)-2-{4-[(phenoxycarbonyl)amino]benzyl}pyrimidin-5-yl)acetate (100 mg, 0.24 mmol) and 4-fluorobenzyl alcohol (60 mg, 0.48 mmol) in N,N-diisopropylethylamine (0.17 mL, 0.95 mmol) and tetrahydofuran (2 mL) was refluxed for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the remaining residue was purified by preparative TLC (chloroform/methanol 30:1) to give methyl {4-(dimethylamino)-2-[4-({[(4-fluorobenzyl)oxy]carbonyl}amino)benzyl]pyrimidin-5-yl}acetate (45 mg, 42%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.C(Cl)(Cl)(Cl)Cl.[N+:28]([C:31]1[CH:48]=[CH:47][C:34]2[NH:35][C:36]3[C:37](=[CH:40][NH:41][C:42](=[O:46])[C:43]=3[C:44]#[N:45])[S:38](=O)[C:33]=2[CH:32]=1)([O-:30])=[O:29]>CN(C)C=O>[N+:28]([C:31]1[CH:48]=[CH:47][C:34]2[NH:35][C:36]3[C:37](=[CH:40][NH:41][C:42](=[O:46])[C:43]=3[C:44]#[N:45])[S:38][C:33]=2[CH:32]=1)([O-:30])=[O:29]
Reactant: N#Cc1c2c(c[nH]c1=O)S(=O)c1cc([N+](=O)[O-])ccc1N2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1c2c(c[nH]c1=O)Sc1cc([N+](=O)[O-])ccc1N2
Reaction time: 0.25 h

Procedure:
To a solution of 27 parts of triphenylphosphine in a mixture of 195 parts of acetonitrile with 400 parts of carbon tetrachloride is added 12 parts of a 1:1 solvate of 2,3-dihydro-8-nitro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile 10-oxide with N,N-dimethylformamide. The resultant mixture is heated at the boiling point under reflux with stirring for 15 minutes, then chilled. The precipitate which forms is isolated by filtration and recrystallized from a mixture of N,N-dimethylformamide and methanol to give 2,3-dihydro-8-nitro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile solvated 2:1 with N,N-dimethylformamide which melts above 305°. The solvent of crystallization can be removed by heating at around 200° in vacuo.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:12][CH2:13][N:14]([CH2:22][CH2:23]Cl)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+]>CS(C)=O.ClCCl>[Br:1][C:2]1[C:3]([C:8]2([C:9]#[N:10])[CH2:23][CH2:22][N:14]([C:15]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:21])[CH2:13][CH2:12]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ncccc2Br)CC1
Temperature: 18 °C
Reaction time: 18 h

Procedure:
The (3-bromopyridin-2-yl)acetonitrile (2.00 g, 10.2 mmol) and tert-butyl bis(2-chloroethyl)carbamate (2.46 g, 10.2 mmol) were dissolved in 102 mL of DMSO. The reaction was purged with a stream of nitrogen and cooled to 18° C. To this reaction was added sodium hydride (0.564 g, 22.3 mmol), which was then warmed to 50° C. and stirred for 18 hours. The mixture was diluted with dichloromethane (150 mL), washed with water (3×150 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 5-30% EtOAc in hexanes to yield tert-butyl 4-(3-bromopyridin-2-yl)-4-cyanopiperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([Cl:10])=[C:4]([S:11][CH2:12][CH2:13][NH2:14])[N:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([Cl:10])=[C:4]([S:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[N:3]=1
Reactant: N#Cc1nc(Cl)c(SCCN)nc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCSc1nc(N)c(C#N)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of Example 9 above, 2-amino-5-chloro-3-cyano-6-[(2-aminoethyl)thio]pyrazine (50 mg), was suspended in pyridine (0.5 ml), to which acetic anhydride (0.5 ml) was then added. The reaction mixture was stirred at room temperature overnight (18 hours), after which ice was added. The product precipitated, was filtered, and washed with water (10 mg).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[C:6]([CH:10]1[CH:15]([OH:16])[CH2:14][CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11]1)([O:8][CH3:9])=[O:7]>CCOCC>[C:6]([CH:10]1[CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13][CH2:14][CH:15]1[O:16][CH:1]([CH3:2])[O:3][CH2:4][CH3:5])([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C1CC(C)(C)CCC1O
Reactant: C=COCC
Solvent: CCOCC
Product: CCOC(C)OC1CCC(C)(C)CC1C(=O)OC
Yield: 98 %

Procedure:
Ethyl vinyl ether (10.5 g) were added slowly and dropwise to 50 ml of Et2O containing 6-carbomethoxy-4,4-dimethylcyclohexan-1-ol (25 g) at 0° C. under nitrogen. After 30 minutes the mixture was washed with saturated aqueous NaHCO3. After distillation (Bp 110-120° C./10 torr) were obtained 34 g of 2-carbomethoxy-4,4-dimethyl-1-(2-methyl-1,3-dioxapent-1-yl)cyclohexane (yield 98%)