Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][NH2:16])(=[O:12])=[O:11])([O-:3])=[O:2].[Cl:17][CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[Cl:17][CH2:18][CH2:19][S:20]([NH:16][CH2:15][CH2:14][NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])(=[O:22])=[O:21]
Reactant: NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCNS(=O)(=O)CCCl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of N-(2-nitrobenzenesulfonyl)ethylenediamine, 2-chloroethanesulfonyl chloride, triethylamine, and methylene chloride was stirred at 0° C. for 3 hours to yield N-(2-{[(2-chloroethyl)sulfonyl]amino}ethyl)-2-nitrobenzenesulfonamide. This compound was dissolved in acetonitrile, here were added cesium carbonate and tetrabutylammonium iodide, and the mixture was stirred at 80° C. for 21 hours to yield 5-[(2-nitrophenyl)sulfonyl]-1,2,5-thiadiazepane 1,1-dioxide. This compound was dissolved in acetonitrile, here were added 4-methylbenzenethiol and potassium carbonate, and the mixture was stirred at 50° C. for 21 hours to yield 1,2,5-thiadiazepane 1,1-dioxide.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]=[C:16]([NH:19][C:20](=[O:36])[CH2:21][C:22]3[C:30]4[C:29](=[O:31])[N:28]([CH3:32])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=4[O:24][C:23]=3[CH3:35])[S:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[C:37]([O:43][CH2:44]Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>CC(C)=O>[CH3:39][C:38]([CH3:41])([CH3:40])[C:37]([O:43][CH2:44][N:15]1[C:14]([C:5]2[CH:6]=[CH:7][C:8]([O:9][C:10]([F:13])([F:11])[F:12])=[C:3]([Cl:2])[CH:4]=2)=[CH:18][S:17][C:16]1=[N:19][C:20](=[O:36])[CH2:21][C:22]1[C:30]2[C:29](=[O:31])[N:28]([CH3:32])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=2[O:24][C:23]=1[CH3:35])=[O:42]
Reactant: Cc1oc2c(c1CC(=O)Nc1nc(-c3ccc(OC(F)(F)F)c(Cl)c3)cs1)c(=O)n(C)c(=O)n2C
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na]
Solvent: CC(C)=O
Product: Cc1oc2c(c1CC(=O)N=c1scc(-c3ccc(OC(F)(F)F)c(Cl)c3)n1COC(=O)C(C)(C)C)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared by the reaction of sodium salt of N-{4-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide (2.0 g, 0.0036 mol) with chloromethyl pivalate (0.82 g, 0.005455 mol) in dry acetone (60 ml) to yield 390 mg of product as an off white solid. 1H NMR (300 MHz, CDCl3) δ 1.22 (s, 9H), 2.34 (s, 3H), 3.33 (s, 3H), 3.53 (s, 3H), 4.11 (s, 2H), 6.49 (s, 2H), 7.24 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.98 (s, 1H). ESI-MS (m/z): 642.75 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[CH:21][CH:20]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(Cl)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 3 of Example 12, and 4-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [C:1]([O:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28]C(N)=S>CN(C)C=O>[C:2]1([C:1]2[O:9][C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[N:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(C(=O)C(OC(=O)c2ccccc2)c2ccccc2)cc1
Reactant: NC(N)=S
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2nc(-c3ccccc3)oc2-c2ccccc2)cc1
Temperature: 160 °C

Procedure:
0.5 g of 2-[4-(dimethylamino)phenyl]-2-oxo-1-phenylethyl benzoate is dissolved in 10 ml of dimethylformamide in a reactor. 0.212 g of thiourea (2 eq.) is subsequently added and the reaction mixture is left to react at reflux (160° C.) for 6 hours.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C([BH3-])#N.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)c2c1CNCC2
Temperature: 25 °C

Procedure:
Alternatively, a solution of 5-bromo-8-nitroisoquinoline (1.0 g) in glacial acetic acid (30 mL) was cooled to 0° C. and, before freezing, was treated with sodium cyanoborohydride (1.10 g). The reaction mixture was warmed slowly to room temperature under nitrogen. The reaction mixture was diluted with water and basified. Organic layer extracts were chromatographed on silica gel as before.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].C([Li])(C)(C)C.CCCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>C1COCC1>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[B:20]([OH:25])[OH:21]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cccc(Br)c1C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cccc(B(O)O)c1C
Temperature: -78 °C
Yield: 185.2 %

Procedure:
To a solution of 3-bromo-o-xylene (500 mg, 2.7 mmol) in THF (15 mL) at −78° C. under N2 was slowly added 1.7 M tert-butyl lithium in pentane (1.77 mL, 3.0 mmol). This was stirred at −78° C. for 30 m. To the reaction mixture was added B(OiPr)3 (2.05 g, 11 mmol), and the reaction mixture was raised to 20° C. and stirred for 2 h. 3 N HCl (10 mL) was added to the reaction mixture and the acidic solution was stirred for 90 m. The reaction mixture was extracted using EtOAc (4×50 mL), and the organic solution was extracted using a 1 N solution of NaOH (100 mL). The aqueous solution was washed with Et2O (2×50 mL), acidified to pH 1 using concentrated HCl, and then extracted using EtOAc (4×50 mL). The organic solution was then washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to afford 2,3-dimethylphenylboronic acid compound (750 mg, 45%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[O:10]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(I)c1Cl
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1nccc(-c2ccc(Oc3ccccc3)cc2)c1Cl
Temperature: 150 °C

Procedure:
To a mixture of intermediate compound D6 (0.5 g, 1.826 mmol) in 1,4-dioxane (11.25 ml) under a nitrogen atmosphere were added 4-phenoxyphenyl boronic acid [C.A.S. 51067-38-0] (0.469 g, 2.191 mmol), Pd(PPh3)4 (0.105 g, 0.0913 mmol) and NaHCO3 (3.75 ml, aqueous sat. solution). The reaction mixture was subjected to microwave heating at 150° C. for 5 min. After cooling, the mixture was filtered through a pad of diatomaceous earth and washed with EtOAc. The filtrate was evaporated in vacuo and the residue was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D36 (0.498 g, 86%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[CH:4]2)(=[O:23])=[O:22]
Reactant: Cn1ncc2cc(CO)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc2cc(COS(C)(=O)=O)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1-methyl-1H-indazol-5-yl)methanol (0.15 g, 0.92 mmol) was dissolved in dichloromethane (3 mL), cooled to 0° C. and treated with triethylamine (0.14 mL, 1.0 mmol, 1.1 equiv) and methanesulfonyl chloride (0.079 mL, 1.0 mmol, 1.1 equiv). After stirring for 2 hours, the mixture was treated with additional triethylamine (0.14 mL, 1.0 mmol, 1.1 equiv) and methanesulfonyl chloride (0.079 mL, 1.0 mmol, 1.1 equiv). After an additional 1 hour, the mixture was diluted with dichloromethane (100 mL), washed with sodium bicarbonate (15 mL, aqueous saturated) and brine (15 mL), dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][S-:26].[Na+]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:26][CH3:25])=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: C[S-]
Agent: [Na+]
Product: CSc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 25 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-(5-methylsulfanyl-thiazol-2-yl)-urea (94 mg, 25%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and sodium methanethiolate (140 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.[NH:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33]1>>[Br:1][C:2]1[C:7]([N:32]2[CH2:37][CH2:36][CH2:35][C@H:34]([NH2:38])[CH2:33]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Product: N[C@H]1CCCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 22.32 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (S)-tert-butyl piperidin-3-ylcarbamate, 289 was obtained as an off-white solid (17.8 mg, 22.32%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.31 (d, J=1.8 Hz, 1H), 9.23 (s, 1H), 9.03 (s, 1H), 8.60 (d, J=4.7 Hz, 1H), 8.46 (d, J=7.9 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.62 (dd, J=11.8, 7.1 Hz, 1H), 7.52 (dd, J=8.0, 4.8 Hz, 1H), 3.92 (d, J=10.0 Hz, 1H), 3.84 (d, J=11.7 Hz, 1H), 2.89 (dt, J=16.9, 10.7 Hz, 2H), 2.82-2.75 (m, 1H), 1.96 (d, J=12.6 Hz, 1H), 1.90-1.71 (m, 2H), 1.27 (dd, J=20.9, 9.6 Hz, 1H); ESI MS m/z=450.1 (M+1)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([NH2:15])([CH3:14])[CH2:12][NH2:13]>CO>[NH2:15][C:11]([CH3:14])([CH3:10])[CH2:12][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(N)CN
Solvent: CO
Product: CC(C)(N)CNc1ccc(C#N)cc1
Yield: 87.3 %

Procedure:
4-Fluorobenzonitrile (7.0 g, 58 mmol) and 2-methylpropane-1,2-diamine (14 g, 160 mmol) were heated in a sealed vial in a microwave reactor (Biotage) at 180° C. for 25 minutes in two batches. Each batch was dissolved in methanol (50 mL) and then concentrated with silica to dryness. Flash chromatography on silica of each batch with neat acetonitrile and 2% triethylamine in acetonitrile as eluents gave 4-(2-amino-2-methylpropylamino)benzonitrile (9.58 g, 88% combined yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.S(Cl)([Cl:15])=O>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:10]([Cl:15])=[O:12])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1ncc(Cl)c(C(=O)Cl)n1
Yield: 91.7 %

Procedure:
With stirring, 15 g of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid were added a little at a time to 40.8 g (25 ml, 0.34 mol) of thionyl chloride and 0.47 g (0.5 ml, 6.5 mmol) of N,N-dimethylformamide, and the reaction mixture was then heated under reflux until a marked evolution of gas was no longer noticeable. The mixture is taken up in a little methylene chloride. Concentration gives 15 g of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carbonyl chloride, which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])C.[CH:17]1([C:23]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:20]3[CH:19]=[CH:18][C:17]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:22][CH:21]=3)[CH:12]=2)[NH:7][C:6]=1[C:4]([OH:3])=[O:5]
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1Cl
Product: O=C(O)c1[nH]c2ccc(-c3ccc(C4CCCCC4)cc3)cc2c1Cl

Procedure:
The sub-title compound was prepared in accordance with Example 1(a) from 5-bromo-3-chloroindole-2-carboxylic acid ethyl ester (see Example 35, Method 1, step (a)) and 4-cyclohexylphenylboronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]=[N:10][NH:9]1.[CH3:14][N:15]([CH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[C:16](Cl)=[O:17]>CN(C)C1C=CN=CC=1>[CH3:14][N:15]([CH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[C:16]([N:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[N:9]=[N:10]1)=[O:17]
Reactant: CN(C(=O)Cl)C1CCSCC1
Reactant: O=c1nn[nH]n1-c1ccccc1Br
Agent: CN(C)c1ccncc1
Product: CN(C(=O)n1nnn(-c2ccccc2Br)c1=O)C1CCSCC1

Procedure:
Similarly to the process described in Example 1, 2.5 g (10 mmol) of 1-(2-bromophenyl)-1,2-dihydro-5H-tetrazol-5-one, 2 g (10 mmol) of N-methyl-N-(tetrahydro-2H-thiopyran-4-yl)carbamoyl chloride and 1.5 g (12 mmol) of 4-dimethylaminopyridine were reacted. Yield 2.5 g.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1
Reactant: O=S(Cl)Cl
Reactant: O=C1Nc2ccccc2SC1CCO
Product: O=C1Nc2ccccc2SC1CCCl
Yield: 72.7 %

Procedure:
By a process similar to that in Reference Example 13, 2-(2-hydroxyethyl)-2H-1,4-benzothiazin-3(4H)-one was allowed to react with thionyl chloride to give 2-(2-chloroethyl)-2H-1,4-benzothiazin-3(4H)-one. The yield was 72.7%. Recrystallization from methanol gave prisms, m.p. 133°-133.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][N:21]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:22]=4[CH:23]([CH3:25])[CH3:24])[C:14]3=[O:33])[N:9]=[C:10]([C:11]#[N:12])[C:3]=12.CCO.[CH2:37](N)[CH2:38][NH2:39]>CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][N:21]([C:26]5[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=5)[C:22]=4[CH:23]([CH3:24])[CH3:25])[C:14]3=[O:33])[N:9]=[C:10]([C:11]3[NH:39][CH2:38][CH2:37][N:12]=3)[C:3]=12
Reactant: NCCN
Reactant: CC(C)c1c(N2CCC(n3nc(C#N)c4c(N)ncnc43)C2=O)cnn1-c1ccc(F)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1c(N2CCC(n3nc(C4=NCCN4)c4c(N)ncnc43)C2=O)cnn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
A mixture of 4-amino-1-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carbonitrile (0.055 g, 0.12 mmol) in ethane-1,2-diamine (1.5 mL), HOAc (0.23 mL), and EtOH (2.0 mL) was stirred at 100° C. for 45 min. The mixture was then cooled to room temperature, quenched with sat. aq. NaHCO3 (50 mL), and extracted with IPA:CHCl3 (1:2 v/v, 100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-[4-amino-3-(4,5-dihydro-1H-imidazol-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.057 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([O:27][C:18]3[C:17]4[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=4)[N:21]=[CH:20][CH:19]=3)=[CH:29][C:30]=2[CH3:35])=[S:12])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 56%).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[S:17](Cl)(=[O:19])=[O:18])([O-:7])=[O:6].C(Cl)(Cl)Cl>N1C(C)=CC=CC=1C>[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[S:17]([O:4][CH2:3][CH2:2][F:1])(=[O:19])=[O:18])([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: OCCF
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCCF)c([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
To a solution of 2-fluoroethanol (1.28 g, 20 mmol) in 2,6-lutidine (20 mL) at −10° C. was added 2,4-dinitrobenzene-1-sulfonyl chloride LVI (4.91 g, 18.7 mmol) in portions. A precipitate formed so CHCl3 (50 mL) was added to the reaction mixture in order to ensure efficient stirring. After 10 min, the mixture was washed with cold 10% aqueous HCl (150 mL) and water (2×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1:2 EtOAc:hexane) to afford 2-fluoroethyl 2,4-dinitrobenzenesulfonate LVII (1.44 g, 4.90 mmol, 24%).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[Li]C.C(=O)=O.CC(C)=O.[Cl:17][C:18]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([C:28](=[O:30])[CH3:29])=[CH:20][N:19]=1>CCOCC.Cl[Ti](Cl)(Cl)Cl>[Cl:17][C:18]1[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[C:21]([C:28]([OH:30])([CH3:1])[CH3:29])=[CH:20][N:19]=1
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C=O
Agent: [Li]C
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)(O)c1cnc(Cl)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a 1.0 M solution of TiCl4 in toluene (6.67 mL, 6.67 mmol) was added a 1.6 M solution of MeLi in Et2O (4.18 mL, 6.69 mmol) dropwise a −78° C. (dry ice/acetone bath). The resulting dark solution stirred at −78° C. for 30 minutes. A solution of 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (500 mg, 2.23 mmol) in Et2O (3 mL) was added dropwise at −78° C. The reaction was slowly allowed to warm to rt in the dewar over a 15 h period. TLC analysis showed complete conversion to the more polar tertiary alcohol product. The mixture was then cooled to 0° C. and quenched with sat. aq. NH4Cl (10 mL) followed by EtOAc (10 mL) for the workup. The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (2×10 mL). The EtOAc layers were combined, dried using Na2SO4 and evaporated to give the crude product. Purification using ISCO FCC eluting with 20% EtOAc in Hexanes gave 459 mg of 2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (86% yield) as a colorless oil. LC-MS MS (ESI) m/z 241.12 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 9.05 (s, 1H), 1.99 (s, 1H), 1.67 (s, 6H).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11](=[O:26])[C:12]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:27]([O:31][C:32]([NH:34][C@H:35]([C:57](O)=[O:58])[CH2:36][S:37][C:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11](=[O:26])[C:12]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:17][CH2:16][N:15]([C:57](=[O:58])[C@H:35]([CH2:36][S:37][C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:33])[CH2:14][CH2:13]1
Reactant: Cc1ccccc1CC1(C(=O)OCc2ccccn2)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: Cl
Product: Cc1ccccc1CC1(C(=O)OCc2ccccn2)CCN(C(=O)[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OC(C)(C)C)CC1

Procedure:
4-(2-methylbenzyl)isonipecotic acid 2-pyridylmethyl ester bis HCl salt was coupled to N-t-butoxycarbonyl-S-trityl-L-Cysteine utilizing the procedure described in Example 1, Step 7 to afford the product as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[C:34]([CH3:41])=[C:35]([CH:39]=O)[NH:36][C:37]=2[CH3:38])[CH2:28][CH2:27]1)(=[O:25])[CH3:24]>C(O)C.N1CCCCC1>[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[C:34]([CH3:41])=[C:35](/[CH:39]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:36][C:37]=2[CH3:38])[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCN(Cc2c(C)[nH]c(C=O)c2C)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=O)N1CCN(Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (357 mg, 1 mmol) was condensed with 4-(4-acetyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (263 mg, 1 mmol) in ethanol (3 mL) and piperidine (3 drops) at 95-100° C. for 2 hours to give the titled compound.