Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:6]2[O:11][CH:10]=[CH:9][C:7]=2[N:8]=1.ClC1N=C(Cl)C2OC=CC=2N=1.N1CCNCC1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1.C(Cl)Cl>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:14][CH2:13]2)[C:6]2[O:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1nc(N2CCNCC2)c2occc2n1
Agent: C1CNCCN1
Agent: Cl
Agent: Clc1nc(Cl)c2occc2n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(c2nc(Cl)nc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a flask was added 2-chloro-4-(piperazin-1-yl)furo[3,2-d]pyrimidine, hydrochloride salt (0.325 g, 1.18 mmol, prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [Ark Pharm] with piperazine), DCM (7 mL), pyridine (7.00 mL) and MsCl (0.101 mL, 1.29 mmol). The mixture was stirred overnight at rt. The mixture was warmed to about 35° C. and stirred for about 5 h. The solvent was removed in vacuo and the residue dissolved in DCM (20 mL). The organics were washed with water (about 20 mL) and with saturated aqueous NaHCO3 (about 20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with an elution gradient EtOAc/hexanes (50 to 75%) to give 2-chloro-4-(4-(methylsulfonyl)piperazin-1-yl)furo[3,2-d]pyrimidine (0.162 g, 43%): LC/MS (Table 2, Method a) Rt=1.11 min; MS m/z 317.2 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10]([CH2:11][C@@H:12]([OH:22])[CH2:13][CH2:14]2)=[CH:9][CH2:8]3)[CH2:5][CH2:4]1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C.O>CC(C)=O>[CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[C:9](=[O:25])[CH2:8]3)[CH2:5][CH2:4]1
Reactant: CC(C)=O
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: C=C[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.75 h

Procedure:
A solution of pregna-5,20-dien-3β-ol (300.5 mg, 1.000 mmol) in 35 mL of acetone was cooled in an ice water bath and 2.67 M Jones reagent (0.71 mL, 1.9 mmol) was added. After stirring 11/2 h a further 0.71 mL of Jones reagent were added and the reaction was continued 45 min, 2-Propanol (1.0 mL) was added and the mixture was poured into 100 mL of water. The mixture was then extracted twice with 50 mL of ethyl acetate and the combined organic extracts were washed with 50 mL of saturated sodium bicarbonate +50 mL of water +50 mL of brine and filtered through a 21 mm dia×22 mm high column of silica gel 60. The column was eluted further with 25 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization of the residue from 95% ethanol gave a light yellow powder (104.6 mg, 0.3348 mmol 33%), m.p. 114-120° C.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl.[CH:34](N(C(C)C)CC)(C)[CH3:35].C(Cl)(=O)C=C>O1CCOCC1.C(Cl)Cl>[CH2:24]([O:23][C:20]1[N:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6](=[O:5])[CH:34]=[CH2:35])[CH2:9][CH2:10]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1)[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(OCCc3ccccc3)nc2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(OCCc3ccccc3)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
[1-(6-Phenethyloxy-pyridine-3-sulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.18 g, 0.39 mmol) was suspended in a 4M solution of HCl in Dioxane (10 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum and the resulting residue dissolved in THF (10 ml). To this solution was added diisopropylethylamine (0.34 ml, 1.99 mmol) was added in one portion, followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 50% DCM, 50% EtOAc) to give the title compound (0.032 g, 19% yield) as a white solid.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=1[NH2:14].C(OCC)(=O)C.CCCCCCC>O>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=1[NH:14][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c(NC(=O)C2CCCCC2)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
1 ml (7.62 mmol, 1.1 eq.) of cyclohexanoic acid chloride is added to a solution of 1.05 g (6.89 mmol) of 2,5-dimethoxyaniline in 10 ml of a mixture toluene/methanol (1/1). The reaction mixture is maintained under stirring at 70° C. for 1.5 hour, and, after returning to ambient temperature, is poured into 50 ml of water. The expected product is extracted twice with 50 ml of toluene, then washed twice with 50 ml of water. The organic phases are combined, dried over magnesium sulphate and the solvent evaporated off under reduced pressure. 1.46 g (yield=67%) of N-(2,5-dimethoxyphenyl)cyclohexanecarboxamide is obtained and used without other purification in the following stage.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:28])[C:26]#[CH:27])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.ClCCl.CO.N>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:28])[C:26]#[C:27][C:2]3[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: C#CC(=O)NCc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: OCc1ccc(I)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(CO)cc1)NCc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.2.a. from 4-iodobenzyl alcohol and propynoic acid-(4′-chlorobiphenyl-4-yl)methylamide. Yield: 0.52 g (90% of theory); C23H18ClNO2 (M=375.85); calc.: molecular ion peak (M+H)+: 376/378; found: molecular ion peak (M+H)+: 376/378; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[C:26]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][C:17]=1[Cl:27].[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH:2]([OH:1])[CH2:3][N:23]3[CH2:22][CH2:21][C:20]4[CH:19]=[CH:18][C:17]([Cl:27])=[C:16]([Cl:15])[C:26]=4[CH2:25][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Clc1ccc2c(c1Cl)CCNCC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: OC(COc1cccc2[nH]ccc12)CN1CCc2ccc(Cl)c(Cl)c2CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=405 (M+ of free base). α[D]589 =-6.87 (c=0.44, methanol).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:24]=O)[C:18]=2[CH:17]=[CH:16]1.[NH:26]1[CH2:29][CH2:28][CH2:27]1>C1COCC1.ClCCl.C([O-])(O)=O.[Na+]>[N:26]1([CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH:17]=[CH:16][NH:15]3)[CH2:29][CH2:28][CH2:27]1
Reactant: C1CNC1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1cc(CN2CCC2)c2cc[nH]c2c1
Reaction time: 1 h

Procedure:
Sodium triacetoxy borohydride (1.46 g, 6.9 mmol) was added to a solution of 1H-indole-4-carbaldehyde (0.5 g, 3.4 mmol) and azetidine (0.39 g, 6.87 mmol) in THF (15 ml). The mixture was stirred for 1 h and diluted with dichloromethane and NaHCO3 (aq). The organic phase was washed with brine (1×), dried (MgSO4) and evaporated. The crude product was dissolved in dichloromethane and hexane was added (1:1). The off white powder was filtered and washed with a mixture of dichloromethane hexane (1:1). Yield: 400 mg (52%). Off white solid. MS (ESI+) for C12H14N2 m/z 187 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH2:26][CH2:27][CH3:28])([CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11](=O)[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[CH:9][CH:10]=1.[CH2:29]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH2:26][CH2:27][CH3:28])([CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11](=[CH2:29])[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[CH:9][CH:10]=1
Reactant: C1CCOC1
Reactant: CCCC(O)(CCC)CCc1cccc(C(=O)CCNC(=O)OC(C)(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C(CCNC(=O)OC(C)(C)C)c1cccc(CCC(O)(CCC)CCC)c1
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide in THF is added KOBu-t (1 M in THF, 6.1 mmol) at room temperature. After stirring for 30 mins, tert-butyl 3-(3-(3-hydroxy-3-propylhexyl)phenyl)-3-oxopropylcarbamate is added. The resulting mixture is stirred at room temperature for 18 h. The reaction is quenched by the addition of AcOH. The mixture is filtered and concentrated under reduced pressure. Purification by flash chromatography (15 to 50% EtOAc-hexanes gradient) gives tert-butyl 3-(3-(3-hydroxy-3-propylhexyl)phenyl)but-3-enylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:26]=1[O:34][CH3:35]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:26]=3[O:34][CH3:35])=[CH:8][S:7][C:6]=2[CH:17]=1
Reactant: Clc1ccc2c(Nc3ccncc3)csc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN(c1ccncc1)c1csc2cc(Cl)ccc12
Temperature: 45 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
6-Chloro-3-(4-pyridinylamino)benzo[b]thiophene (4 g, 15 mmol) was added portionwise as a powder to a suspension of sodium hydride (60% oil dispersion, 0.7 g, 18 mmol, washed with heptane) in 50 mL of dimethylformamide. After the anion formation was completed, 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4 g, 16 mmol) was added. The reaction mixture was stirred two hours at 45° C., and then was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, and then was dried (anhydrous magnesium sulfate), filtered and concentrated to 8 g of a dark oil. Elution through silica with 10% methanol in ethyl acetate via flash column chromatography afforded 4.1 g of a brown oil. Elution of this oil three times through silica with ethyl acetate via flash column chromatography afforded 3.0 g of a waxy solid. Recrystallization from acetonitrile afforded 2.1 g of white crystals, mp 148°-149° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]1[C:19]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:20])[C:11]=2[CH:10]=[CH:9][C:8]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:2]([O:21][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:17](=[C:16]([F:20])[CH:15]=[CH:14][CH:13]=3)[CH2:18][C:19]=2[C:7]=1[F:6])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Oc1ccc2c(c1F)Cc1c(F)cccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCOc1ccc2c(c1F)Cc1c(F)cccc1-2

Procedure:
56 mmol of 1-bromobutane are added to a mixture of 36 mmol of 1,8-difluorofluoren-2-ol and 109 mmol of anhydrous potassium carbonate in 250 ml of 2-butanone (methyl ethyl ketone) and the mixture is subsequently heated to reflux for 8 h. The still hot solution is then mixed with 50 ml of water. The phases are separated, the organic phase is washed with water and saturated sodium chloride solution and dried over sodium sulfate, and the solvent is removed on a rotary evaporator. The purification is effected by filtration through aluminum oxide (neutral) using toluene as the eluent and recrystallization from heptane. 2-Butoxy-1,8-difluorofluorene is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]5)[C:19]([CH:36]=[CH2:37])=[CH:18][CH:17]=4)=[N:14][N:13]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:10]3=[CH:11][N:12]=2)[CH:2]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:36]([C:19]1[C:20]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]2)=[N:21][C:16]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:14]=2)=[CH:17][CH:18]=1)[CH3:37]
Reactant: C=Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
(S)-tert-butyl 1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-vinylpyridin-2-yl)piperidin-3-ylcarbamate (59.18 mg, 0.09426 mmol) and palladium hydroxide on carbon 20% (0.2:0.8, Palladium hydroxide:carbon black, 6.619 mg) in Ethanol (30 mL) in a round bottom flask was vacuumed and connected to a Hydrogen balloon. The mixture was stirred at room temperature over the weekend. The reaction mixture was filtered through Celite. The filtrate was concentrated to afford (S)-tert-butyl 1-(3-ethyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate, which was dissolved in Trifluoroacetic Acid (3 mL) and Methylene chloride (3 mL), and treated with Trifluoromethanesulfonic acid (83.4 uL, 0.943 mmol) and Triethylsilane (150.6 uL, 0.943 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 327 as an off-white solid (5.8 mg, 15%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.31 (s, 1H), 9.20 (s, 1H), 9.13 (s, 1H), 8.59 (d, J=4.5 Hz, 1H), 8.46 (d, J=8.0 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.53 (dd, J=8.0, 4.8 Hz, 1H), 3.60 (d, J=11.4 Hz, 2H), 2.86 (dt, J=20.8, 9.5 Hz, 2H), 2.70 (dd, J=18.0, 10.0 Hz, 2H), 1.95 (d, J=12.5 Hz, 1H), 1.84 (d, J=13.1 Hz, 1H), 1.80-1.69 (m, 1H), 1.26 (t, J=7.5 Hz, 3H); ESI MS m/z=400.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([F:17])[F:16])[CH2:10][CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([N:27]([CH:37]2[CH2:39][CH2:38]2)CC2C=CC(OC)=CC=2)[C:24]2=[N:40][CH:41]=[C:42]([C:43]#[N:44])[N:23]2[N:22]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([F:17])[F:16])[CH2:10][CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH:37]2[CH2:38][CH2:39]2)[C:24]2=[N:40][CH:41]=[C:42]([C:43]#[N:44])[N:23]2[N:22]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(CC(F)F)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCN(CC(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To the stirred solution of 2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)-piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (120 mg, 0.194 mmol) in dry dichloromethane (2.0 mL) was added anisole (0.1 mL, 0.915 mmol) and trifluoroacetic acid (0.3 mL, 3.87 mmol) at room temperature. The reaction mixture stirred at room temperature for overnight. On completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was separated and aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give off-white solid. This was purified by preparative HPLC to afford 2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg, 0.098 mmol, 50.5% yield) as an off-white solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1ccc(F)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 62.1 %

Procedure:
A mixture of (3-chloro-4-fluorophenyl) boronic acid (300 mg, 1.72 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (331 mg, 1.89 mmol), K2CO3 (474 mg, 3.44 mmol) and Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) in THF (2 mL) and H2O (1 mL) was heated at 80° C. in a sealed tube for 3 h. The mixture was cooled to rt and partitioned between EA (20 mL) and H2O (20 mL). The aqueous layer was extracted with EA (20 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel elute with PE to give 2-chloro-1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (240 mg, 62.3% yield) as colorless oil.
Reaction SMILES: Cl.[CH2:2]([NH:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](=O)[C:12]([CH3:14])=[O:13]>O.C(Cl)Cl>[CH2:2]([NH:9][N:10]=[CH:11][C:12](=[O:13])[CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)C=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)C=NNCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of benzylhydrazine hydrochloride (11.1 g, 57.1 mmol) in water (100 mL) was added dropwise a solution of pyruvaldehyde (10.3 g, 9.3 mL, 57.1 mmol) in water (500 mL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (4×150 mL). The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to provide 2-oxopropanal benzylhydrazone (10.1 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:3]=1.[H][H]>C1(C)C=CC=CC=1.[Pt](=O)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1C=Cc1cccc(Br)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(Br)cc1CCc1cccc(Br)c1

Procedure:
The product from step (iii) (8.5 g) and platinum(iv)oxide (0.87 g) in toluene (150 ml) was stirred under 1 atmosphere of hydrogen for 72 hours. The mixture was filtered and the filtrate evaporated under reduced pressure. Yield 6. 1 g.
Reaction SMILES: [Na:1].[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[O:6])[CH3:3].[C:18](O)(=[O:23])[CH2:19][C:20](O)=[O:21].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:2]([N:4]1[C:18](=[O:23])[CH2:19][C:20](=[O:21])[N:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[C:5]1=[O:6])[CH3:3].[Na:1]
Reactant: CCNC(=O)Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC(=O)O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCN1C(=O)CC(=O)N(c2ccc(S(=O)(=O)O)cc2)C1=O
Temperature: 95 °C
Yield: 93.5 %

Procedure:
A mixture of 26.6 g of N-ethyl-N'-(4-sulfophenyl)urea sodium salt, 13.5 g of malonic acid and 150 ml of glacial acetic acid was heated and dissolved at 60° to 70° C. Acetic anhydride (200 ml) was added dropwise to the solution with stirring. After addition of the acetic anhydride, the temperature of the reaction solution increased to 95° C. The reaction solution was stirred for 6 hours and then condensed under reduced pressure so as to precipitate crystals. 700 ml of ethanol was added to the condensed solution and the crystals were completely precipitated. The precipitated crystals were collected by filtration, washed thoroughly with ethanol and dried by heating under reduced pressure to obtain 31.2 g of crystals. The crystals obtained were recrystallized using a 90% methanol aqueous solution and, thereby, 23.5 g of white crystals was obtained. Melting point: 290° C.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:30])[CH:11]=1)=[O:9].C(N(C(C)C)CC)(C)C.[O:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][NH2:66])[CH2:60][CH2:59]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][NH:66][C:38](=[O:39])[CH2:37][CH2:36][S:35][CH2:34][C:33]2[CH:32]=[C:31]([CH:43]=[CH:42][CH:41]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[C:3]([C:2]([F:47])([F:1])[F:48])[CH:4]=2)=[O:9])=[O:30])[CH2:60][CH2:59]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1)NCCN1CCOCC1
Reaction time: 24 h
Yield: 38.8 %

Procedure:
A solution of 25 mg of 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoic acid 1.1, 19 mg of diisopropylethylamine, and 6 mg of 2-morpholinoethylamine in 1 mL of DMF was treated with 15 mg of HATU and stirred for 24 h. The product was isolated by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to give 11.3 mg of product. MS (ES, m/z): 789 [M+H]+