Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH:18](OC)[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[NH4+]>C(Cl)Cl>[CH:1]([N:14]1[CH2:15][CH:16]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[NH:21][CH:20]=2)[CH2:17]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(c1c[nH]c2ccc(C#N)cc12)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC[SiH](CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2[nH]cc(CC3CN(C(c4ccccc4)c4ccccc4)C3)c2c1
Yield: 86 %

Procedure:
A solution of 3-[(1-benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole-5-carbonitrile, triethylsilane (5.5 ml, 34 mmol) and trifluoroacetic acid (6.6 mL, 86 mmol) in methylene chloride (40 mL) was refluxed overnight. The reaction was poured into ice and neutralized with concentrated ammonium hydroxide. The mixture was extracted with methylene chloride (3×100 mL). The organic layer was washed with water (3×80 mL), dried over anhydrous sodium sulfate, filtered and solvent removed under vacuum. The crude oil was column chromatographed on a Biotage (40% ethyl acetate-hexane/hexane). The product-containing fractions were concentrated under vacuum to give 0.56 g (86%) of the title compound as a clear oil. MS ES m/e 378 (M+H)+; 1H NMR (500 MHz, DMSO-D6): 2.74-2.78 δ (M, 3 H), 2.96 δ (d, J=6.7 Hz, 2 H), 3.21 δ (t, J=6.4 Hz, 2 H), 4.4 δ (s, 1 H), 7.15-7.17 δ (m, 2H), 7.24-7.29 δ (m, 5 H), 7.38-7.418 δ (m, 5 H), 7.47 δ (d, J=8.4 Hz, 1 H), 8.07 δ (s, 1 H), 11.37 δ (br, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:15]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[Cl:30])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCl.N>C(O)C>[ClH:1].[CH2:15]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:3]3[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:25][C:24]=1[Cl:30])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: CN(C)c1cc2c(Cl)ncnc2cn1
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: CN(C)c1cc2c(Nc3ccc(OCc4ccccc4)c(Cl)c3)ncnc2cn1
Product: Cl

Procedure:
Prepared according to Procedure A from 4-chloro-6-(N,N-dimethylamino)pyrido[3,4-d]pyrimidine and 4-benzyloxy-3-chloroaniline (prepared according to the published method: WO96/09294); tlc (dichloromethane:ethanol:aq. ammonia, 100:8:1) Rf 0.48; m/z (M+1)+406.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:9]=1.CN(C)[CH:20]=[O:21]>>[OH:21][CH2:20][C:17]1[CH:16]=[CH:15][S:14][C:13]=1[C:11]1[S:12][C:8]([CH:7]=[O:6])=[CH:9][CH:10]=1
Reactant: CN(C)C=O
Reactant: OCc1ccc(-c2cccs2)s1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2sccc2CO)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Phosphorus oxychloride ("POCl3 ") (1 ml) was added into dimethyl formamide (20 ml) slowly under nitrogen gas atmosphere in ice bath and stirred for 1 hour. The dimethyl formamide solution (5 ml) of 5-hydroxymethyl-2,2'-bithiophene (0.5 g) was dropped in slowly. The mixture was stirred for half an hour at room temperature, then the temperature was raised to 50° C. and was further stirred for 3 hours. The reaction solution was poured into potassium carbonate ice water solution. Then the solution was extracted with 100 ml of ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residual solid was purified by column chromatography, eluted with ethyl acetate/n-hexane (3/7). Light yellowish product was recrystallized from ethyl acetate/n-hexane mixture. The melting point of the product was 123°-124° C. The yield was 85%.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][S:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: NCc1ccc(Br)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1ccc(Br)s1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
To a stirred suspension of 1-(5-bromo-2-thienyl)methanamine (1.00 g) in dichloromethane (15 mL) were slowly added 2-chlorobenzenesulfonyl chloride (1.18 g) and N,N-diisopropyl ethyl amine (0.76 g) at 0° C. After 15 min the ice bath was removed and the mixture was stirred at r.t. for 1.5 h. The mixture was diluted with dichloromethane and washed with 0.5 M HCl and with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 95:5 to ethyl acetate) to give N-(5-bromo-thiophen-2-ylmethyl)-2-chloro-benzenesulfonamide (0.83 g) as a colorless solid. MS: 363.9 ([M−H]−)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=CC(S(O)(=O)=O)=[CH:6][CH:7]=1.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.CC(CCO)=C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:3][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[O:17][CH2:6][CH:7]=1
Reactant: O=C1CCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)CCO
Solvent: Cc1ccccc1
Product: CC1=CCOC2(CCCC2)C1
Temperature: 115 °C
Yield: 56 %

Procedure:
A mixture of p-TSA (20 g, 0.105 mol) and toluene (2 L) was heated to 115° C. To this mixture were added cyclopentanone (840 g, 10 mols) and isoprenol (946 g, 11 mols) and heated further for 3-6 h. Water was removed from the reaction azeotropically. The reaction mixture was then cooled to room temperature. The organic phase was washed with a 5% Na2CO3 solution, washed with water dried and concentrated and distilled further to provideto 9-methyl-6-oxaspiro[4.5]dec-8-ene (0.851 kg) having a purity of 95% (sum of the isomers) for a total yield of 56%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:11][C:4]1[N:3]=[C:2]([N:22]2[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.9 %

Procedure:
A solution of 2,6-dichloro-3-nitro-pyridine (1.47 g, 7.61 mmol) in toluene (40 mL) was treated with, solid K2CO3 (1.26 g, 9.13 mmol) and 4-methyl-piperidine (0.90 mL, 7.6 mmol). The reaction was stirred at room temperature for 1.5 h, additional toluene (10 mL) was added, and the reaction was stirred an additional 5 h. The reaction was diluted with EtOAc and washed with water. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (2.00 g, 100%) as a waxy, bright yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.06 (d, 1H, J=4.0 Hz), 7.61 (d, 1H, J=4.0 Hz), 3.83-3.75 (m, 2H), 3.08-2.97 (m, 2H), 1.77-1.68 (m, 2H), 1.57 (br s, 1H), 1.37-1.23 (m, 2H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C11H14ClN3O2, 256.1 (M+H), found 256.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9](Cl)(Cl)Cl)=[CH:4][CH:3]=1.Br[C:14]1[CH:19]=[CH:18][CH:17]=C[N:15]=1>C(N)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:18][CH:19]=[CH:14][N:15]=2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Sc1ccc(Br)cc1
Reactant: Brc1ccccn1
Solvent: NC=O
Solvent: O
Product: Brc1ccc(Sc2ccccn2)cc1
Temperature: 75 °C
Yield: 64.5 %

Procedure:
A solution of (4-bromophenyl)(trichloromethyl)sulfane (0.25 g, 0.816 mmol) in 12 mL of formamide was degassed with nitrogen and treated with 2-bromopyridine (0.078 ml, 0.816 mmol). The reaction solution was heated at 75° C. overnight. Then it was cooled to room temperature and diluted with water, extracted with DCM, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluted with 1-5% of EtOAc in 20% DCM/heptanes (v/v), affording 0.14 g (65% yield) of 2-((4-bromophenyl)thio)pyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:5])C=O.Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[NH:16]1C=CN=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>O>[NH:16]1[CH:1]=[N:2][C:5]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:17]1
Reactant: O=C(CBr)c1ccccc1
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(Cc1nc[nH]n1)c1ccccc1
Yield: 85 %

Procedure:
To 20 ml of dimethylformamide, 1.99 g of bromoacetophenone, 0.69 g of triazole, and 2 g of potassium carbonate were added, and the mixture was allowed to react at room temperature for 16 hours. The reaction mixture was poured into 100 ml of water, and the deposited crystals were collected by filtration, which were recrystallized from ethyl acetate/hexane to obtain the desired compound (yield: 85%).
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][CH2:5][S:6]([OH:9])(=O)=[O:7].[CH2:10]([NH2:12])[CH3:11].C(O)C>C(OCC)C.C(N(CC)CC)C>[CH2:10]([N:12]1[CH2:3][CH2:4][CH2:5][S:6]1(=[O:9])=[O:7])[CH3:11]
Reactant: CCN
Reactant: O=S(=O)(O)CCCCl
Agent: [Cl-]
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCN1CCCS1(=O)=O
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 24 g of chloride of 3-chloropropanesulfonic acid in 150 ml ethyl ether is added drop-by-drop a solution of 12 g ethylamine and 10 ml ethyl ether. The addition of the ethylamine solution is carried out under stirring and with cooling with the aid of an ice bath. After addition of the solution, the stirring is continued for 1 hour. A white precipitate of ethylamine chlorhydrate forms, which is removed by filtration upon fritted glass. Ethyl ether is removed by evaporation under reduced pressure and, to the residue obtained, is added a mixture of 4.8 g soda pellets, 400 ml ethanol and 12.5 g triethylamine. The mixture is subjected to reflux for 2 hours. After cooling, the solvent is evaporated and the residue is distilled under vacuum. There is obtained 14.2 g (yield: 70%) of N-ethylpropanesultam (boiling point under 0.1 torr: 88° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(F)cc1
Product: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1

Procedure:
The title compound was prepared from 2,4-dichloropyrimidine and 1-ethynyl-4-fluorobenzene using methods analogous to those described in Example 2 (65%). TLC (25% EtOAc/hexanes): Rf=0.21. mp 125-126° C. IR: 3049 (w), 2210 (w), 1559 (s). 1H NMR (CDCl3): 8.61 (d, J=5.0 Hz, 1H), 7.70-7.60 (m, 2H), 7.38 (d, J=5.0 Hz, 1H), 7.13-7.06 (m, 2H). 13C NMR (CDCl3): 163.99 (d, JC-F=252 Hz), 161.86, 159.66, 153.39, 134.96 (d, JC-F=8.6 Hz), 121.77, 116.96 (d, JC-F=3.4 Hz), 116.40 (d, JC-F=22 Hz), 95.27, 85.89. Anal. Calcd for C12H6ClFN2: C, 61.95; H, 2.60; N, 12.04. Found: C, 62.15; H, 2.83; N, 12.00.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(O)(O)(=O)=O.Cl[C:27]1[NH:28][CH2:29][CH2:30][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH3:20][N:2]([CH3:1])[S:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:27]3[NH:31][CH2:30][CH2:29][N:28]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: ClC1=NCCN1
Reactant: CN(C)S(=O)(=O)c1ccc(Cc2ccc(N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(C)O
Product: CN(C)S(=O)(=O)c1ccc(Cc2ccc(NC3=NCCN3)cc2)cc1
Yield: 164.4 %

Procedure:
A mixture of 4-(4-dimethylaminosulfonylbenzyl)-phenylamine (288 mg) and 2-chloro-imidazoline sulfate (110 mg) in 2-propanol was heated under reflux for 16 hours. A dilute solution of potassium carbonate was poured into the mixture and extracted with dichloromethane (4×15 mL). Solvents were evaported to give 2-[4-(4-dimethylaminosulfonylbenzyl)-phenyl]amino-imidazoline as a solid (320 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2[O:39][C:38]([NH2:40])=[N:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:37]4[N:36]=[C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[O:39][C:38]4=[NH:40])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: Nc1nnc(-c2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4nc(-c5ccccc5)oc4=N)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[N:29]([CH3:39])[C:30]([CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[N:31][CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[N:29]([CH3:39])[C:30]([CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[N:31][CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Cn1c(C(=O)Oc2ccccc2)cnc1CN1CCCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cnc(CN4CCCC4)n3C)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 3-methyl-2-pyrrolidin-1-ylmethyl-3H-imidazole-4-carboxylic acid phenyl ester, the title compound was obtained as off-white solid (76% yield). MS: m/e=457(M+H+), mp 255° C.
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20]Cl)[CH:5]=1)(=[O:3])[CH3:2].[CH3:22][OH:23]>Cl([O-])(=O)(=O)=O.[Ag+]>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20][O:23][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(CCl)c(OCCCCCCC#N)cc1O
Reactant: CO
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: COCc1cc(C(C)=O)c(O)cc1OCCCCCCC#N
Temperature: 25 °C

Procedure:
Approximately 3 millimoles of the chloro compound of Example 127 were treated with 0.62% g of silver perchlorate in 50 ml of methanol at 0° C. The reaction mixture was allowed to warm to room temperature over a 2 hour period. The mixture was then partitioned between ethyl acetate and an acidic sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 1:1 ethyl acetate/hexane providing 50 mg of the title compound. NMR, MS.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])C.O=C([O-])[C@@H:7]([C@H:9]([C@H:11]([C@@H:13]([C:15]([O-:17])=[O:16])[OH:14])[OH:12])[OH:10])[OH:8].[C:19]1([CH2:27][NH3+:28])[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH3+:26])[CH:20]=1.[CH3:29][OH:30]>>[O:30]=[C:29]([O:3][CH3:1])[C@@H:7]([C@H:9]([C@H:11]([C@@H:13]([C:15]([O:17][CH3:19])=[O:16])[OH:14])[OH:12])[OH:10])[OH:8].[Cl-:4].[Cl-:4].[C:19]1([CH2:27][NH3+:28])[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH3+:26])[CH:20]=1
Reactant: CC(=O)Cl
Reactant: O=C([O-])[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: CO
Agent: [NH3+]Cc1cccc(C[NH3+])c1
Product: COC(=O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)OC
Product: [Cl-]
Yield: 88.94 %

Procedure:
Acetyl chloride (2 mL) was added drop-wise over a period of 5 min to methanol (25 mL) maintained in an ice-bath. m-Xylylenediammonium galactarate (14, 1.008 g, 2.910 mmol) was then to the solution and the reaction was allowed to reflux for 4 h. Within 1 h complete dissolution had occurred. The solvent was removed under reduced pressure and the remaining white powder dried under vacuum at room temperature for 16 h to give white solid 1:1 dimethyl galactarate/m-xylylenediammonium dichloride (20, 1.158 g, 2.588 mmol, 88.94%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[CH:9][C:8]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:30](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:17]1([C:15]2[NH:14][N:13]=[C:12]([N:11]3[C:10]4[CH:9]=[C:8]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]=4[N:1]=[CH:30]3)[CH:16]=2)[CH2:19][CH2:18]1
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)c(C(N)=O)c1)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(C(N)=O)c2ncn(-c3cc(C4CC4)[nH]n3)c2c1)c1ccc(F)cc1
Yield: 11.1 %

Procedure:
The mixture of (S)-2-amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)benzamide (Method 100, 3.95 g, 10 mmol) and formamidine acetate (2.2 g, 21 mmol) in EtOH (50 ml) was heated at reflux for 36 hours. After cooling, the reaction mixture was treated with saturated sodium bicarbonate solution (30 ml) and EtOAc (80 ml). The organic layer was separated, washed with brine (30 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc-MeOH=30:1) to give the title compound as an off-white solid (0.45 g, 11%). 1H NMR (400 MHz) 12.79 (s, 1H), 9.00 (d, J=2.8 Hz, 1H), 8.42 (s, 1H), 7.67 (d, J=2.8 Hz, 1H), 7.43 (m, 2H), 7.38 (d, J=2.0 Hz, 1H), 7.09 (m, 3H), 6.59 (d, J=6.4 Hz, 1H), 6.16 (d, J=1.6 Hz, 1H), 4.54 (m, 1H), 1.97 (m, 1H), 1.43 (d, J=6.4 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 404; Found: [M+H]+ 405.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Reactant: NCc1ccccn1
Solvent: CC(=O)O
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1ccccn1

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (0.20 mmol, 42 mg) and 2-aminomethyl-pyridine (0.20 mmol, 22 mg) in glacial acetic acid (1 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The crude product was used without purification.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][N:7]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:8]1([C:14](=[O:17])[NH:15][OH:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>ClCCl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([O:27][C:24]2[CH:23]=[CH:22][C:21]([S:18]([N:7]([C:8]3([C:14](=[O:17])[NH:15][OH:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH2:6][CH2:5][C:4]([OH:35])=[O:3])(=[O:19])=[O:20])=[CH:26][CH:25]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)CCN(C1(C(=O)NO)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCN(C1(C(=O)NO)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (15.1 mmol) of the product from Step G in dichloromethane is concentrated by rotary evaporation with the addition of 75 mL of toluene. This solution is treated with 75 mL of water, cooled to 0° C., and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets over 10 minutes with vigorous stirring. This mixture is stirred for 15 minutes at 0° C. and warmed to ambient temperature over one hour. The aqueous phase is separated, diluted with 7.5 mL of tetrahydrofuran, cooled to 0° C., and treated with 33 mL of 6N aqueous hydrochloric acid over 20 minutes. This mixture is stirred with 75 mL of ethyl acetate at 0° C. to ambient temperature, and the ethyl acetate phase is separated and washed with water. The ethyl acetate solution was concentrated to yield the title compound.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH3:7][O:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](SC)=[CH:13][CH:12]=1.[CH3:20]O>O>[CH3:7][O:8][C:9](=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([S:3]([CH3:20])(=[O:5])=[O:2])=[CH:15][CH:16]=1
Reactant: O=S([O-])OO
Reactant: COC(=O)Cc1ccc(SC)cc1
Reactant: CO
Agent: [K+]
Solvent: O
Product: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of oxone 30.7 g (50 mmol) was added drop by drop in 80 mL of water to a solution of 3.4 g (17.3 mmol) of the compound obtained in example 1 in 100 mL of methanol keeping the reaction in a water/ice bath. Once added, agitation continues for 5 h, allowing temperature to get room level. Then, part of the solvent is concentrated at reduced pressure and the precipitated solid is filtered washing with water repeatedly. After drying, this solid weighs 3 g. Waters from filtering are extracted with dichloromethane, the organic phase is washed with water, dried on sodium sulfate anhydride and concentrated in a rotary evaporator obtaining 1 more g of product than expected, yield 4 g (17 mmol, 100% yield). This solid melts with decomposition at 57° C. and its purity is 99% by HPLC. Spectroscopic data confirm the expected structure:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][CH2:8][N:9]([CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:35]([N:37]=[C:38]([N:40]1CCNCC1)[S-])#[N:36].O.[NH2:47]N>>[NH2:47][C:38]1[NH:37][C:35]([N:13]2[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]([O:21][CH3:22])=[O:20])[CH2:8][CH2:7][C:6]3[CH:27]=[CH:28][C:3]([Cl:2])=[CH:4][CH:5]=3)[CH2:11][CH2:12]2)=[N:36][N:40]=1
Reactant: COC(=O)c1ccccc1CN(CCc1ccc(Cl)cc1)C1CCNCC1
Reactant: N#CN=C([S-])N1CCNCC1
Reactant: NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccccc1CN(CCc1ccc(Cl)cc1)C1CCN(c2nnc(N)[nH]2)CC1

Procedure:
Methyl 2-(((4-chlorophenethyl)(piperidin-4-yl)amino)methyl)benzoate hydrochloride obtained in Step 2 was reacted with K2CO3 and S,S′-dimethyl-N-cyano-dithioiminocarbonate, followed by the cyclization of the intermediate (N-cyanopiperazine-1-carbimidothioate) with hydrazine monohydrate in a manner described in Procedure 3. ESI MS for C24H29ClN6O2: calculated 468.99. found 469.4/471.4 (M+1), 467.3/469.3 (M−1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[I:10]I.[OH-].[K+]>CN(C=O)C>[I:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: c1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99.4 %

Procedure:
In a 50 mL round-bottomed flask, indazole (0.80 g, 6.8 mmol) was dissolved in DMF (14 mL). Iodine (3.4 g, 13.5 mmol) was added followed by potassium hydroxide (1.47 g, 26.2 mmol). The dark reaction mixture was stirred at room temperature for 1.25 h then was quenched with 10% aq NaHSO3 and extracted with diethyl ether (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 1.65 g (95%) of 3-iodo-1H-indazole as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 10.56 (br. s, 1H), 7.47-7.57 (m, 3H), 7.23-7.30 (m, 1H).