Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:27](=O)[CH2:28][CH2:29][CH2:30][CH3:31])[C:23](OC)=[O:24])=[CH:17][CH:16]=1)#[N:8]>ClC1C=CC(Cl)=CC=1Cl>[CH2:28]([C:27]1[N:2]2[N:1]=[CH:5][N:4]=[C:3]2[NH:6][C:23](=[O:24])[C:22]=1[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[C:9]([C:7]#[N:8])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][CH:19]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: Nc1nc[nH]n1
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Yield: 52.6 %

Procedure:
A solution of 1H-1,2,4-triazol-3-amine (1.5 g) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (7.1 g) in 1,2,4-trichlorobenzene (70 mL) was stirred at 190° C. for 6 hr. After evaporation of the solvent under reduced pressure, ethyl acetate was added to the obtained residue. The precipitated solid was collected by filtration to give the title compound as a colorless solid (3.6 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4([CH3:27])[CH2:26][CH2:25]4)=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][C@@H:10]2[N:28]([CH3:32])[C:29](Cl)=[O:30])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:33]1([CH2:36][CH2:37][NH:38][CH3:39])[CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[CH:33]1([CH2:36][CH2:37][N:38]([CH3:39])[C:29]([N:28]([C@@H:10]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][N:12]([C:14]([CH:16]3[CH2:17][CH2:18][N:19]([C:22]([C:24]4([CH3:27])[CH2:25][CH2:26]4)=[O:23])[CH2:20][CH2:21]3)=[O:15])[CH2:11]2)[CH3:32])=[O:30])[CH2:35][CH2:34]1
Reactant: CNCCC1CC1
Reactant: CN(C(=O)Cl)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(CCC1CC1)C(=O)N(C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Yield: 71.7 %

Procedure:
To a solution of rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid chloride (250 mg, 0.50 mmol) in THF (1 mL) was added (2-cyclopropyl-ethyl)-methyl-amine (99 mg, 1.0 mmol) and N,N-diisopropyl ethyl amine (256, 1.50 mmol). The solution was irradiated in the microwave for 900 sec. at 130° C. before it was diluted with ethyl acetate (15 mL) and washed with an aqueous solution of sodium carbonate (1 M, 15 mL). The organic layer was separated and washed with brine (15 mL) and the aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2,ethyl acetate:methanol=100:0 to 85:15) afforded the title compound (202 mg, 72%) as a white foam. MS m/e: 563.4 [M]+.
Reaction SMILES: Cl[C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35](OC)=[CH2:36])=[CH:31][N:30]=3)([CH3:28])[CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[CH:15]=[N:16][CH:17]=1.C(N(CC)CC)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([C:29]3[N:30]=[CH:31][C:32]([C:35]4[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:36]=4)=[CH:33][CH:34]=3)([CH3:28])[CH:25]([CH3:26])[CH3:27])=[CH:22][CH:23]=2)[CH:15]=[N:16][CH:17]=1
Reactant: C=C(OC)c1ccc(C(C)(c2ccc(-c3cncc(OC)c3)cc2)C(C)C)nc1
Reactant: CCOC(=O)C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(C(C)(c3ccc(-c4cncc(OC)c4)cc3)C(C)C)nc2)on1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Ethyl 2-chloro-2-(hydroxyimino)acetate (116 mg, 0.768 mmol) was added to a stirred solution of 3a (0.256 mmol) and triethylamine (357 μL, 2.56 mmol) in THF (10.0 mL) at rt. After approximately 1 h, the reaction mixture was acidified to ˜pH 1 by the addition of TFA, and the resulting mixture was heated to 50° C. for approximately 4.5 h. The reaction mixture was cooled to rt, neutralized with saturated aqueous sodium bicarbonate and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-100% EtOAc/hexanes as eluent) to afford the title compound 3b. m/z (ES) 472 (MH)+. 1HNMR (500 MHz, CDCl3): δ 9.05 (d, 1H, J=2.3 Hz), 8.46 (d, 1H, J=2.4 Hz), 8.29 (d, 1H, J=2.5 Hz), 8.00 (dd, 1H, J=2.3, 8.5 Hz), 7.51 (m, 4H), 7.41 (d, 1H, J=8.2 Hz), 7.36 (m, 1H), 6.98 (s, 1H), 4.50 (q, 2H, J=7.1 Hz), 3.92 (s, 3H), 3.71 (m, 1H), 1.78 (s, 1H), 1.47 (t, 3H, J=7.1 Hz), 0.91 (d, 3H, J=6.7 Hz), 0.88 (d, 3H, J=6.9 Hz).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]2[CH2:22][C:23](O)=[O:24])#[N:9].ClC(OCC)=O.[BH4-].[Na+].Cl>CO.O1CCCC1>[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]2[CH2:22][CH2:23][OH:24])#[N:9]
Reactant: Cn1c(=O)cc(CC(=O)O)c2cc(C#N)ccc21
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(=O)cc(CCO)c2cc(C#N)ccc21
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
0.22 ml (1.58 mmol) of triethylamine is added to a suspension of 0.365 g (1.51 mmol) of 6-cyano-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetic acid in 10 ce of tetrahydrofuran at -10° C., and 0.16 ml (1.6 mmol) of ethyl choroformate is then added dropwise. After stirring at -10° C. for 45 minutes, the reaction medium is filtered and the solids are rinsed with 3×8 ml of tetrahydrofuran. 0.25 g (6.61 mmol) of sodium borohydride and then 0.94 ml of methanol are added to the filtrate at 5-10° C. After stirring at 5-10° C. for 2 hours, 13 ml of 1 N aqueous hydrochloric acid solution are added. The mixture is extracted with is dichloromethane and then with ethyl acetate. The organic phases are dried over sodium sulphate and then concentrated under vacuum.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][SH:22].S([O-])([O-])(=O)=O.[Mg+2].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CO>[Si:1]([O:8][CH2:9][C:10]1[S:22][C:21]([C:20]([O:24][CH3:25])=[O:23])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)c1ccccc1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1sc(CO[Si](C)(C)C(C)(C)C)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 167 (8.924 g, 32.5 mmol) in THF was added methyl thioglycolate (4.36 mL, 48.8 mmol) and stirred 2 hours at room temperature. MAGNESIUM SULFATE (3.91 g, 32.5 mmol) was added and the reaction mixture was stirred for 1 hour. Then CESIUM CARBONATE (10.60 g, 32.5 mmol) in 30 mL of MeOH was added and stirred for an additional 2 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by silica gel chromatography (0%-5% ethyl acetate in hexanes) to yield 168 in 54% (6.389 g) as an orange solid
Reaction SMILES: Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([CH3:26])[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:27]1([C:33]2[CH2:37][C:36]3([CH2:42][CH2:41][CH2:40][NH:39][CH2:38]3)[O:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[CH3:25][N:22]1[CH2:23][CH2:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:4]3[N:3]=[C:2]([N:39]4[CH2:40][CH2:41][CH2:42][C:36]5([O:35][N:34]=[C:33]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:37]5)[CH2:38]4)[C:10]([F:11])=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:14][CH:15]=2)([CH3:26])[CH2:20][CH2:21]1
Reactant: CN1CCC(C)(c2ccc(Nc3nc(Cl)c(F)cc3C(N)=O)cc2)CC1
Reactant: c1ccc(C2=NOC3(CCCNC3)C2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(C)(c2ccc(Nc3nc(N4CCCC5(CC(c6ccccc6)=NO5)C4)c(F)cc3C(N)=O)cc2)CC1
Yield: 20.3 %

Procedure:
A solution of 6-chloro-2-(4-(1,4-dimethylpiperidin-4-yl)phenylamino)-5-fluoronicotinamide (40 mg, 0.106 mmol), 3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-ene (42.1 mg, 0.127 mmol), and DIEA (0.074 mL, 0.425 mmol) in NMP (1 mL) was heated at 120° C. for 3 h and at 130° C. for 2 h. The reaction mixture was cooled, diluted with water. The resulting brown solid precipitate was filtered and purified by prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, and extracted with methylene chloride twice. The combined organic factions were washed with water and concentrated to give 12 mg yellow solid. LC-MS: 3.04 min (RT). (M+H)+=557.28. 1H NMR (400 MHz, chloroform-d) δ ppm 10.66 (1H, s), 7.67 (2H, dd, J=6.81, 2.86 Hz), 7.50 (2H, d, J=8.79 Hz), 7.36-7.44 (3H, m), 7.22-7.25 (1H, m), 7.13 (2H, d, J=8.79 Hz), 5.43 (2H, br. s.), 3.79-3.90 (2H, m), 3.69-3.75 (1H, m), 3.57-3.67 (1H, m), 3.32 (1H, d, J=16.70 Hz), 3.05 (1H, d, J=16.70 Hz), 2.27-2.45 (4H, m), 2.22 (3H, s), 1.92-2.13 (4H, m), 1.57-1.79 (4H, m), 1.12 (3 H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:10]([NH:12][C:13](=[N:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])SC)#[N:11]>>[C:10]([NH:12][C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])=[N:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])#[N:11]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: NCCCCCCCN
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCCCCCCN
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.8 %

Procedure:
1,7-Diaminoheptane (5.2 g) was warmed gently until molten and to it was added N-cyano-N'-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]-S-methylisothiourea (2.69 g). After stirring for 15 hours at room temperature the reaction mixture was extracted with ether to remove excess of the diamine starting material and then purified on a silica gel chromatographic column, eluting with isopropanol to give the title compound (1.08 g), m.p. 84°-87° C. (Found: C, 55.0; H, 8.2; N, 27.8; S, 9.0% C16H29N7S requires: C, 54.7; H, 8.3; N, 27.9; S, 9.1%).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:13][C:7]1[C:8]([F:9])=[C:2]([F:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(F)c(F)c1Cl
Reaction time: 48 h

Procedure:
2-Chloro-3,4-difluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44:4733 (1979)). To a solution of 4,5-difluoro-2-nitroaniline (500 mg, 2.87 mmol) in DMF (16 mL) under N2 was added N-chlorosuccinimide (401 mg, 3.00 mmol) in DMF. The reaction was allowed to stir 48 h. The solution was then poured into 75 mL H2O. the cloudy orange suspension which formed was then extracted with 4×25 mL of methylene chloride. The combined organic extracts were washed with 5×20 mL of H2O and 25 mL sat'd NaCl solution. The organic phase was dried (MgSO4) and the drying agent removed by vacuum filtration. The solvent was rotary evaporated to yield a yellow orange oil which crystallized on standing. 1H NMR showed this solid to be mixture of chlorinated product and starting material. The mixture was separated by flash chromatography (silica gel, 3:1 hexanes:ethyl acetate) to yield 162 mg of a yellow crystalline solid (27%). 1H NMR (CDCl3) δ6.60 (br s, 2H, NH2), 8.00 (m, 1H, H-5). There was 17% starting material contamination by NMR.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:48]>>[NH2:48][C:5]1[C:4]2[N:3]=[CH:2][N:1]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: [NH4+]
Reactant: CCCNC(=O)CCCCCn1cnc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCNC(=O)CCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
6-(1H-Imidazo[4,5-c]quinolin-1-yl)-N-propylhexanamide (7.0 g, 26 mmol) was treated with mCPBA (8.68 g, 37.7 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (8.01 g, 42.1 mmol) according to the method described in Part D of Example 8. The crude product was triturated with ethyl acetate and recrystallized twice from methanol:water to provide 2.00 g of 6-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylhexanamide as brown needles, mp 128-130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([O:16][C@H:17]1[CH2:49][N:20]3[C:21](=[O:48])[C@@H:22]([NH:39][C:40]([C:42]4[CH:46]=[C:45]([CH3:47])[O:44][N:43]=4)=[O:41])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][C@@H:30]4[CH2:35][C@@:31]4([C:36](O)=[O:37])[NH:32][C:33](=[O:34])[C@@H:19]3[CH2:18]1)=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:62][C:63]1([S:66]([NH2:69])(=[O:68])=[O:67])[CH2:65][CH2:64]1.Cl.O1CCOCC1>ClC(Cl)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([O:16][C@H:17]1[CH2:49][N:20]3[C:21](=[O:48])[C@@H:22]([NH:39][C:40]([C:42]4[CH:46]=[C:45]([CH3:47])[O:44][N:43]=4)=[O:41])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][C@@H:30]4[CH2:35][C@@:31]4([C:36](=[O:37])[NH:69][S:66]([C:63]4([CH3:62])[CH2:65][CH2:64]4)(=[O:68])=[O:67])[NH:32][C:33](=[O:34])[C@@H:19]3[CH2:18]1)=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1
Reactant: Cc1cc(C(=O)N[C@H]2CCCCCC=C[C@@H]3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](Oc4nc5cc(F)ccc5c5ccccc45)CN3C2=O)no1
Reactant: CC1(S(N)(=O)=O)CC1
Agent: Cc1cc(C(=O)N[C@H]2CCCCC/C=C\[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3(C)CC3)NC(=O)[C@@H]3C[C@@H](Oc4nc5cc(F)ccc5c5ccccc45)CN3C2=O)no1
Agent: Cc1cc(C(=O)N[C@H]2CCCCC/C=C\[C@@H]3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](Oc4nc5cc(F)ccc5c5ccccc45)CN3C2=O)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: Cc1cc(C(=O)N[C@H]2CCCCCC=C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3(C)CC3)NC(=O)[C@@H]3C[C@@H](Oc4nc5cc(F)ccc5c5ccccc45)CN3C2=O)no1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
The product of Example 1f, (2R,6S,13aS,14aR,16aS,Z)-2-(3-fluorophenanthridin-6-yloxy)-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (0.812 g, 1.21 mmol) was dissolved in dichloroethane (12 mL) and 4A sieves were added to the flask. To this mixture was added carbonyldiimidazole (505 mg, 3.11 mmol) and the reaction mixture was heated at 40° C. for 2 h. The reaction mixture was cooled to room temperature and 1-methylcyclopropane-1-sulfonamide (426 mg, 3.15 mmol) was added followed by 1,8-diazabicycloundecene (0.548 ml, 3.64 mmol). The reaction mixture was stirred at room temperature for 3 h. and then cooled to 0° C. and 4 N HCl in dioxane (2.5 mL, 10 mmol) was added. The resulting solid was washed copiously with dichloromethane and the filtrate was washed with 2 N HCl and then water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with acetone/hexane followed by acetone/chloroform to provide the title compound (0.45 g, 47% yield) as a white solid. MS (ESI): m/z=787.2 [M+H]+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:41])[CH:39]=3)[N:34]([C:42]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:33]=2)=[CH:28][CH:27]=1.[CH:61]([N:63]([CH3:93])[C:64]1([C:90](O)=[O:91])[CH2:68][CH2:67][N:66]([CH2:69][C:70](=[O:89])[N:71]2[CH2:76][CH:75]=[C:74]([C:77]3[CH:82]=[CH:81][C:80]([C:83]4[N:88]=[CH:87][CH:86]=[CH:85][N:84]=4)=[CH:79][CH:78]=3)[CH2:73][CH2:72]2)[CH2:65]1)=[O:62].[Li]>CN(C=O)C.CN1CCOCC1>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH:41][C:90]([C:64]4([N:63]([CH:61]=[O:62])[CH3:93])[CH2:68][CH2:67][N:66]([CH2:69][C:70](=[O:89])[N:71]5[CH2:72][CH:73]=[C:74]([C:77]6[CH:78]=[CH:79][C:80]([C:83]7[N:88]=[CH:87][CH:86]=[CH:85][N:84]=7)=[CH:81][CH:82]=6)[CH2:75][CH2:76]5)[CH2:65]4)=[O:91])[CH:39]=3)[N:34]([C:42]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:33]=2)=[CH:30][CH:31]=1
Reactant: CN(C=O)C1(C(=O)O)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Reactant: Nc1ccc2c(c1)c(-c1ccc(F)cc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C=O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1

Procedure:
Added EDCl.HCl (75 mg, 0.39 mmol) and HOBT.H2O (50 mg, 0.37 mmol) to a solution of 3-(4-Fluoro-phenyl)-1trityl-indazol-5-ylamine (110 mg, 0.234 mmol) and 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid, Lithium salt (6T) (95 mg, 0.211 mmol) in DMF (2 ml) and NMM (0.1 ml) at room temperature, then stirred overnight. The solvent was evaporated and residue extracted with MeCl2 (50 ml), washed with H2O (20 ml), dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with v/v 9:1 EtOAc:Hexanes yielding 7T as a white solid (89 mg, 44%) ESMS (MH 901).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]1[N:15]=[CH:14][O:13][N:12]=1.C(N(CC)CC)C.O>C1COCC1>[O:13]1[CH:14]=[N:15][C:11]([CH2:10][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:12]1
Reactant: Nc1ccc(S)cc1
Reactant: ClCc1ncon1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(SCc2ncon2)cc1
Yield: 82.2 %

Procedure:
A solution of 4-aminothiophenol (1.0 g), 3-chloromethyl-1,2,4-oxadiazole (1.0 g) and triethylamine (1.1 ml) in THF (10 ml) was stirred at room temperature for 18 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:3→1:2), to give 4-(1,2,4-oxadiazol-3-ylmethylthio)aniline (1.36 g) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([O:23][CH2:24][CH3:25])(=[O:22])[C:15]#[C:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClC1C=CC=C(Cl)C=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:14]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1oc(-c2ccc(Cl)cc2)ns1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: Clc1cccc(Cl)c1
Product: CCOC(=O)c1snc(-c2ccc(Cl)cc2)c1C(=O)OCC
Temperature: 148 °C
Reaction time: 16 h

Procedure:
Into a 150-mL sealed tube, was placed 5-(4-chlorophenyl)-2H-1,3,4-oxathiazol-2-one (2 g, 9.65 mmol, 1.00 equiv), 1,4-diethyl but-2-ynedioate (3.29 g, 19.33 mmol, 2.00 equiv), 1,3-dichlorobenzene (30 mL). The resulting solution was stirred for 16 h at 148° C. The resulting mixture was concentrated under vacuum. This resulted in 1 g (31%) of 4,5-diethyl 3-(4-chlorophenyl)-1,2-thiazole-4,5-dicarboxylate as brown oil.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:2]=1.C1C=C[C:19]2[N:24](O)[N:23]=[N:22][C:20]=2[CH:21]=1.C(Cl)CCl.N1C=C(N)C=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[NH:23]1[CH:21]=[C:20]([NH:22][C:12]([C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:3]2[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=2)=[O:14])[CH:19]=[N:24]1
Reactant: On1nnc2ccccc21
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Agent: Nc1cn[nH]c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cn[nH]c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(m-tolyl)oxazole-4-carboxylic acid (11.18 g) in DCM (65 mL), HOBT (11.15 g, 0.083 mol) and EDC (15.8 g, 0.083 mol) was added at 0° C. This suspension was stirred at this temperature for 10 min, then it was added to a suspension was of 1H-pyrazol-4-amine (5.48 g) and DIPEA (17.65 mL) in DCM (50 mL). The resulting mixture was allowed to warm to rt and was stirred at rt for 18 h. Percipitation of the desired compound was obtained by the addition of water. The solid was filtered and dried to yield the title compound. LC-MS conditions B: tR=0.63 min, [M+H]+=269.13.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH:30](=O)[CH:31]([CH3:33])[CH3:32]>>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: CC(C)C=O
Agent: Cl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CC(C)C)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1, with racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride from Example 2, Step 1 and isobutyraldehyde instead of acetone. The crude purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C23H32ClN6O (M+H)+: m/z=443.2; Found: 443.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]2[S:10][CH:11]=[C:12](Br)[CH:13]=2)[S:5][CH:6]=1.[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]2[S:10][CH:11]=[C:12]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH:13]=2)[S:5][CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: Brc1csc(/C=C/c2cc(Br)cs2)c1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Product: CCCCCCCCCCCCc1csc(/C=C/c2cc(CCCCCCCCCCCC)cs2)c1
Temperature: 60 °C
Yield: 38 %

Procedure:
A mixture of 16 (1.1 g, 3.14 mmol) and NiCl2(dppp) (0.17 g, 0.31 mmol) was degassed in a 2 necked RBF. Anhydrous THF (25 mL) was then added to the mixture. C12H25MgBr (1M in THF, 8 mL, 8 mmol) was added dropwise to the reaction mixture and heated at 60° C. overnight. The reaction was quenched with 2N aqueous HCl, extracted with CH2Cl2 and filtered through celite. The residue was purified by column chromatography (silica gel, hexane/CH2Cl2, 4:1) and recrystallized from hexane to give a yellow solid compound 17 in 38% yield. 1H-NMR (DCM-d2, 400 MHz) ppm 0.88 (t, 6H, J=6.8 Hz) ppm 1.29 (m, 36H) ppm 1.60 (td, 4H, J=7.2 Hz, J=14.6 Hz) ppm 2.55 (m, 4H) ppm 6.78 (s, 2H) ppm 6.88 (s, 2H) ppm 6.96 (s, 2H).