Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N[C@H](C(O)=O)C(C)C)=O)(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.C1(N)CCCCC1.C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:72][C:73]([C:75]1([NH:80][C:81]([CH:83]2[CH2:87][CH:86]([O:88][C:89]3[C:98]4[C:93](=[CH:94][C:95]([O:99][CH3:100])=[CH:96][CH:97]=4)[N:92]=[C:91]([C:101]4[CH:106]=[CH:105][CH:104]=[CH:103][CH:102]=4)[CH:90]=3)[CH2:85][N:84]2[C:107](=[O:127])[NH:108][CH:109]([C:114](=[O:126])[NH:115][CH:116]2[C:124]3[C:119](=[CH:120][CH:121]=[CH:122][CH:123]=3)CC2O)[C:110](C)([CH3:112])[CH3:111])=[O:82])[CH2:77][CH:76]1[CH:78]=[CH2:79])=[O:74])C>>[CH:124]1([CH2:116][NH:115][C:114]([C@@H:109]([NH:108][C:107]([N:84]2[CH2:85][C@H:86]([O:88][C:89]3[C:98]4[C:93](=[CH:94][C:95]([O:99][CH3:100])=[CH:96][CH:97]=4)[N:92]=[C:91]([C:101]4[CH:106]=[CH:105][CH:104]=[CH:103][CH:102]=4)[CH:90]=3)[CH2:87][C@H:83]2[C:81]([NH:80][C:75]2([C:73]([OH:74])=[O:72])[CH2:77][CH:76]2[CH:78]=[CH2:79])=[O:82])=[O:127])[CH:110]([CH3:111])[CH3:112])=[O:126])[CH2:119][CH2:120][CH2:121][CH2:122][CH2:123]1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: NC1CCCCC1
Product: C=CC1CC1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)NCC1CCCCC1)C(C)C)C(=O)O

Procedure:
N-(tert-butoxycarbonyl)-L-valine was attached to the resin as described for the preparation of compound 16 followed by reaction with cyclohexylamine as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC >95%. M+H+712.3.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Br:26]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C.O>[Br:26][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[S:6][C:7]=1[CH3:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 0 °C
Reaction time: 14 h
Yield: 13.5 %

Procedure:
4,5-Dimethyl-2-(4-trifluoromethyl-phenyl)-thiazole hydrochloride (2.6 g, 8.9 mmol) was suspended in ethyl acetate and ice water. Triethylamine (1.2 ml, 8.9 mmol) was added, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine/ice water 1/1 dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dried in vacuo and dissolved in acetonitrile (30 ml) under an argon atmosphere. The solution was cooled to 0° C., N-bromosuccinimide (2.05 g, 11.5 mmol) and 2,2′-azobis(2-methylpropionitrile) (145 mg, 0.89 mmol) were added and the reaction mixture was stirred at ambient temperature for 14 h. Water was added and the formed precipitate was filtered off, washed with water and dried in vacuo to give yellow crystals. The crystals were purified by column chromatography (silica gel, n-heptane/dichloromethane) to give 385 mg (1.2 mmol, 13%) of the title compound as off-white crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:27])[CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C1CNCC(c2ccc(CC)cc2)C1
Reactant: O=C(Cl)N1CCOCC1
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
10.0 g (36.0 mmol) of ethyl 5-(4-ethylphenyl)piperidine-3-carboxylate and 7.0 g (46.8 mmol, 1.3 eq.) of morpholine-4-carbonyl chloride were reacted according to the General Method 3A. Yield: 12.0 g (89% of theory)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[CH:7]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1)[NH2:16]
Reactant: NN
Reactant: Clc1cc(C2COCCO2)ccn1
Solvent: O
Product: NNc1cc(C2COCCO2)ccn1
Temperature: 0 °C
Yield: 92 %

Procedure:
A mixture of 11.4 g. (57 mmoles) of 1-(2-chloro-4-pyridyl)-1-ethylenedioxyethane in 50 ml. of 98% hydrazine hydrate was heated to reflux for 15 hours. The mixture was cooled at 0° C. for 2 hours and the resulting precipitate was filtered and dried to give 10.3 g. (92%) of the desired compound. The analytical sample was recrystallized from toluene-cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.Cl>CC(O)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)O
Product: Clc1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 84 °C
Yield: 75 %

Procedure:
250 mg of 4,6-dichloropyrimidine and 165 mg of p-chloroaniline were dissolved in 2.5 mL of i-PrOH and 0.25 mL of 37% HCl were added. The mixture obtained was refluxed (84° C.) for 2.5 hours under nitrogen atmosphere. A colorless precipitate was formed which was collected by filtration. 6-Chloro-N-(4-chlorophenyl)pyrimidin-4-amine hydrochloride in the form of colorless crystals was obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[N:14]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3CC(F)(F)F)CC1
Yield: 78 %

Procedure:
The title compound was synthesized in analogy to example 51, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless foam (78%).
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][O:19][N:20]4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:9]=2[CH:37]=1>C(O)C>[NH2:20][O:19][CH2:18][C:15]1[N:14]2[C:8]3[CH:7]=[CH:6][C:5]([Br:4])=[CH:37][C:9]=3[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:11][CH2:12][C:13]2=[N:17][N:16]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is treated at 65° C. with 8-bromo-1-[(phthalimidooxy)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5].O>C1(C)C=CC=CC=1.S(C(CC(OCCCCCCCC)=O)C(OCCCCCCCC)=O)(O)(=O)=O.[Na].C(O)(=O)CCCCCCCCCCCCCCCCC>[C:3]([O-:7])(=[O:6])[CH:4]=[CH2:5].[Zn+2:2].[C:3]([O-:7])(=[O:6])[CH:4]=[CH2:5]
Reactant: C=CC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCOC(=O)CC(C(=O)OCCCCCCCC)S(=O)(=O)O
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(=O)[O-]
Temperature: 15 °C
Reaction time: 2 h
Yield: 117.3 %

Procedure:
In a jacketed kneader made of SUS-316, 10 liters in inner volume, 5,926 g of toluene as an organic solvent and 11.4 g of sodium dioctyl sulfosuccinate (produced by Kao Co., Ltd. and marketed under trademark designation of "Pellex OT-P") as an anionic surfactant were placed, then 1,411 g of zinc oxide was added thereto and stirred to be suspended therein and, with the internal temperature of the kneader kept at 40° C., a solution of 540 g of stearic acid as a higher fatty acid in 1,809 g of toluene was added to the stirred suspension over a period of one hour, and the suspension and the added solution were left reacting for 2 hours. Then, the internal temperature of the kneader was cooled to 15° C. and 2,362 g of acrylic acid was added to the reaction mixture therein gradually over a period of 3 hours so as to elevate the temperature to 35° C. and they were left reacting at 40° C. for 4 hours. The reaction mixture was gradually heated to 50° C. under a reduced pressure so as to allow the pressure to reach 20 Torrs and effect the expulsion of the water formed by the reaction and toluene by distillation over a period of 5 hours and obtain 3,988 g of zinc acrylate containing zinc stearate.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1>CS(C)=O>[S:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:6]([CH2:5][C:1]#[N:2])=[CH:7]1
Reactant: [C-]#N
Reactant: ClCc1csc2ccccc12
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
To a stirred solution of NaCN (1.4 g, 28.5 mmol) in DMSO (8 mL) was added 3-(chloromethyl)-1-benzothiophene (4 gm, 21.9 mmol) in DMSO (6 mL) over 15 min. The reaction mixture was stirred at room temperature for 18 h and then quenched with water and extracted with ether (2×50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography using ethyl acetate-hexane (1:1) to furnish 1-benzothien-3-ylacetonitrile (2.5 g, 65%). 1H NMR (200 MHz, CDCl3): δ 3.69 (s, 2H), 7.25-7.91 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1>>[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])=[CH:27][CH:26]=1
Reactant: NCc1ccncc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCc3ccncc3)cc2n1
Yield: 77 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (96 mg, 0.3 mmol) was converted, using 4-picolylamine instead of aminomethylcyclopropane, to the title compound (95 mg, 77%) which was obtained as a light yellow foam. MS: m/e=410.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[C:9]([CH3:24])[CH:8]=1)[NH2:5].[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[C:9]([CH3:24])[CH:8]=1)[NH:5][C:29]([C:28]1[C:27]([Cl:26])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:36])=[O:30]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.089 mmol, 34 mg) and 2,6-dichlorobenzoyl chloride (0.1 mmol, 21 mg) in dichloromethane (2 mL) was added diisopropylethylamine (0.4 mmol, 70 uL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 15 h at room temperature. The resulting brown solution was diluted with dichloromethane (25 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×25 mL), saturated sodium bicarbonate solution (25 mL), and brine solution (25 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 22 mg (48% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as a viscous oil. ES-HRMS m/e calcd for C25H25Cl2N3O5 (M+Na) 541.1065, found 541.1063.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O>N1CCCCC1.C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[C:7](=[O:13])[NH:8]2
Reactant: O=Cc1ccccn1
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(CCO)c2C1=Cc1ccccn1
Temperature: 90 °C
Yield: 45.9 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (80 mg, 0.45 mmol) and 2-pyridinecarboxaldehyde (60 mg, 0.56 mmol) in 1% of piperidine in ethanol (5 mL) was heated at 90° C. for 8 hours. The reaction mixture was concentrated and the residue was chromatographed on a column of silica gel. It was then triturated with ethyl acetate and hexane to give 55 mg (46%) of 4-(2-hydroxy-ethyl)-3-pyridin-2-ylmethylene-1,3-dihydro-indol-2-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@H:14]4[CH2:16][C@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1.[H-].[Na+].O.Cl.C[C:25]([N:27](C)C)=O>[C-]#N.[Zn+2].[C-]#N>[C:25]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@H:14]4[CH2:16][C@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1)#[N:27]
Reactant: CC(=O)N(C)C
Reactant: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@@H]1C[C@H]21
Agent: Cl
Agent: [C-]#N
Agent: [H-]
Solvent: O
Product: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@H]2C[C@H]2C3)c1
Temperature: 120 °C

Procedure:
(1aS,5aS)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (0.87 g, 2.72 mmol) was dissolved in DMA (10 mL). Sodium hydride (0.109 g, 2.72 mmol) was added, and nitrogen was bubbled through the mixture for 10 min. Zinc(II) cyanide (0.638 g, 5.44 mmol) and palladium tetrakistriphenylphosphine, (0.157 g, 0.136 mmol) were added. The reaction was stirred under microwave heating in a sealed tube at 120° C. for 2 h. Water (25 mL) and 6 M aqueous HCl (1 mL) were added. The mixture was extracted with 25% iPrOH/dichloromethane (3×25 mL) (The biphasic mixture was filtered after the first extraction to clear up an emulsion). The combined organic extracts were dried (MgSO4), filtered, then concentrated. The residue was purified by flash chromatography to give the title compound (0.68 g) as a tan solid. LCMS m/z=267.0 [M+H]+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[C:15]([C:16]4[CH:21]=[C:20]([CH2:22][O:23]C5CCCCO5)[N:19]=[C:18]([NH:30][CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+].CCOCC>O1CCCC1>[CH:31]1([NH:30][C:18]2[N:19]=[C:20]([CH2:22][OH:23])[CH:21]=[C:16]([C:15]3[C:14]([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)=[N:13][N:12]4[C:7]([NH:6][CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[CH:8][CH:9]=[CH:10][C:11]=34)[N:17]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2cc(COC3CCCCO3)nc(NC3CCCC3)n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cc(-c2c(-c3ccc(F)cc3)nn3c(NC4CCCC4)cccc23)nc(NC2CCCC2)n1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a solution of N-cyclopentyl-3-{2-(cyclopentylamino)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-pyrimidinyl}-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (134 mg, 2.23 mmol) in tetrahydrofuran (8 mL) was added hydrochloric acid (4 mL, 4 N aqueous, 32 mmol). After 30 minutes, the solution was made basic with sodium bicarbonate and ether was added. The organic layer was washed with water and brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 to 1:1 hexanes:ethyl acetate) provided {2-(cyclopentylamino)-6-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-4-pyrimidinyl}methanol (80 mg, 71%). This material was taken up in ether and treated with anhydrous hydrochloric acid in ether to yield upon filtration a yellow solid. 1H NMR of hydrochloride salt (CDCl3) δ 8.00–7.94 (broad, 1H), 7.78 (d, 1H), 7.54–7.44 (m, 3H), 7.17 (m, 2H), 6.22 (s, 1H), 6.19 (d, 1H), 6.07 (d, 1H), 4.74–4.60 (broad, 1H), 4.47 (s, 2H), 4.36 (m, 1H), 3.99 (m, 1H), 2.16–2.00 (m, 4H), 1.82–1.59 (m, 12H); 19F NMR (CDCl3) δ −111.26; MS m/z 487 (M+1 of free base).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:14][C@H:13]2[CH2:12][C:11](=O)[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+].C(OCC)(=O)C.CO.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:14][C@H:13]2[CH2:12][CH:11]([NH2:22])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [BH3-]C#N
Reactant: O=C1C[C@@H]2C[C@]2(c2ccc(Cl)c(Cl)c2)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC1C[C@@H]2C[C@]2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of (1S,5S)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one (0.7 g, 2.9 mmol) in methanol (87.5 mL) was added ammonium acetate (22.05 g, 290 mmol), stirred for 15 minutes at room temperature and sodium cyanoborohydride (1.45 g, 23 mmol) was added and the mixture was heated to 60° C. for 2 hours. The reaction was monitored by TLC (ethyl acetate/methanol/triethylamine (89:10:1)). The reaction mixture was concentrated under reduced pressure to remove methanol at 30° C., the crude mass was quenched with water (20 mL) and the aqueous layer was extracted with ethyl acetate (3×75 mL). The aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate (3×75 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 2.4 g of crude oil, which was purified by preparative HPLC to yield 430 mg (66%) of 99% pure product. 1H NMR δ(300 MHz,CD3OD) 0.92-0.98 (2H,m), 1.28 (1H,m), 1.76-1.87 (3H,m), 2.08-2.14 (2H,m), 2.57-2.75 (3H,m), 3.98-4.04 (1H,m),7.10-7.15 (1H,m), 7.35-7.42 (2H,m). 13CNMR(CD3OD) δ: 145.91, 133.24, 131.51, 130.79, 129.78, 129.29, 127.58, 127.05, 54.33, 40.53, 37.67, 35.75, 34.36, 33.54, 31.10, 28.25, 26.08, 25.84, 18.53. Purity: 99.53% (a/a) by HPLC. MS, M+(241).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:6]2[N:7]([CH3:19])[C:8](=[O:18])[CH2:9][N:10](C(=O)C(F)(F)F)[CH2:11][C:5]=2[CH:4]=1.N>CO>[CH3:1][O:2][C:3]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:6]2[N:7]([CH3:19])[C:8](=[O:18])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CN(C(=O)C(F)(F)F)C2
Agent: N
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CNC2
Yield: 77.8 %

Procedure:
A mixture of 7-Methoxy-1-methyl-8-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (2.86 g, 0.00824 mol) and 7.0 M of Ammonia in Methanol (30 mL) were reacted in an analogous manner to example 736-D to give an oil. 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro[e][1,4]diazepin-2-one It was triturated with diethyl ether giving 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (1.61 g, 77%). Mp 145-149° C.; LCMS (m/e) 252 (M+1); 1H-NMR (DMSO, 400 MHz) δ 7.91 (s, 1H), 7.41 (s, 1H), 3.94 (s, 2H), 3.79 (s, 1H), 3.31 (s, 3H), 3.25 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=O)[CH2:9]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1O)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1O)C2
Yield: 108.5 %

Procedure:
A mixture of 6-(2-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.04 g), aminoguanidine hydrochloride (0.02 g), concentrated hydrochloric acid (0.041 ml), water (0.041 ml) and ethanol (10 ml) was refluxed for 3 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 4-guanidinoimino-6-(2-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 26) (0.06 g) as colorless crystals.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]C(=O)C(F)(F)F.Br[CH2:17][CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[O:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:9][CH:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17]1
Reactant: CCOC(=O)C=CCBr
Reactant: O=C(Nc1ccccc1O)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1COc2ccccc2N1
Temperature: 0 °C

Procedure:
650 ml of ethanol are introduced into a 3 l reactor, with magnetic stirring, cooled to 0° C., 5.9 g (0.259 mol) of sodium are added slowly, in small portions, followed by successive dropwise addition of 53 g (0.259 mol) of N-(2-hydroxyphenyl)trifluoroacetamide and 50 g (0.259 mol) of 75% pure ethyl 4-bromo-2-butenoate, and the mixture is heated at 80° C. for 1.5 h.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][C:4]1(N)[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]1[N+:11]([O-:13])=[O:12].Cl[C:18]([O:20][CH2:21][CH2:22][Cl:23])=[O:19].CCCCCC>O1CCOCC1>[Cl:23][CH2:22][CH2:21][O:20][C:18](=[O:19])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:16])([F:15])[F:1])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: NC1=CC([N+](=O)[O-])C(N)(CC(F)(F)F)C=C1
Reactant: O=C(Cl)OCCCl
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=C(Nc1ccc(CC(F)(F)F)c([N+](=O)[O-])c1)OCCCl
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of N1 -(2,2,2,-trifluoroethyl)-2-nitro-p-phenylene-diamine (6) (0.705 g, 3 mmol), 2-chloroethyl chloroformate (0.515 g, 3.6 mmol) and CaCo3 (0.40 g, 4 mmol) in dioxane (10 ml) was stirred at 80° C. for 20 minutes, filtered and washed with ethyl acetate. The combined filtrate was washed with water and brine, dried (Na2SO4), and evaporated to give a brown oil. Trituration with hexane gave 2-chloroethyl-N-[4-(2,2,2-trifluoroethyl)-3-nitrophenyl]-carbamate (8) as an orange solid. The unpurified carbamate (8) was dissolved in aqueous ethanol (ETOH: H2O, 15/5 ml) and powdered KOH (1.35 g) was added. The mixture was stirred at 90° C. for 20 minutes and then poured onto crushed ice (20 g) . The resultant mixture was extracted with ethyl acetate, washed with water and brine, dried (Na2SO4), and evaporated to give 0.544 g (65% yield) of N1 -(2,2,2-trifluoroethyl)-N4 -(2-hydroxyethyl)-2-nitro-p-phenylenediamine (9): mp 93°-95° C.; MS m/e 279(M+); 1HNMR (acetone-d6), δ3.25 (m, 2H), 3.76 (m, 2H), 3.91 (bs, 1H), 4.34 (m, 2H), 4.98 (bs, 1H), 7.19 (m, 2H), 7.35 (s,1H), 7.80 (bs, 1H).