Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].[C:13]1(C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(NC)C1C=CC=CC=1>[CH2:3]([N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccccc1
Reactant: CN(C)C=Nc1ccncc1O
Agent: CNCc1ccccc1
Product: CN(C=Nc1ccncc1O)Cc1ccccc1

Procedure:
4-[[(Dimethylamino)methylene]amino]-3-pyridinol (3.0 g) was refluxed in N-benzyl-N-methylamine (6.12 ml) and dry toluene (60 ml) overnight. The reaction mixture was concentrated, adhered to silica (MeOH), flash chromatographed (10% MeOH/EtOAc) and concentrated to give 4.4 g of 4-[[(N-benzyl-N-methylamino)methylene]amino]-3-pyridinol.
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:12]1[N:16]2[CH:17]=[C:18]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:32][CH2:31][CH:30]([C:33]([O:35]C)=[O:34])[CH2:29][CH2:28]4)=[N:25][CH:26]=3)[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH3:37])[CH3:11].O.[OH-].[Li+].C(O)(=O)C>C1COCC1.O>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:12]1[N:16]2[CH:17]=[C:18]([C:21]3[CH:26]=[N:25][C:24]([N:27]4[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]4)=[N:23][CH:22]=3)[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH3:37])[CH3:11]
Reactant: COC(=O)C1CCN(c2ncc(-c3ccc4nc(C)c(C(C)c5ccccc5OC(F)F)n4c3)cn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc2ccc(-c3cnc(N4CCC(C(=O)O)CC4)nc3)cn2c1C(C)c1ccccc1OC(F)F
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of Example 308 (0.28 g, 0.54 mmol) in THF (4 mL) at room temperature was added lithium hydroxide monohydrate (0.04 g, 0.81 mmol) in water (1 mL). The mixture was stirred for 2 h. The solution was adjusted to pH 6 by dropwise addition of acetic acid. The volatiles were removed in vacuo and the residue was treated with acetone (2 mL), causing a thick solid precipitate to form. The mixture was filtered and washed on the sinter with water and acetone, then dried in vacuo, to give the title compound (0.216 g, 79%) as a white solid. δH (400 MHz, DMSO-d6) 8.59 (s, 2H), 8.59 (s), 8.33 (s, 1H), 8.33 (s), 7.56 (dd, 1H, J 7.5, 1.3 Hz), 7.45 (m, 2H), 7.33 (m, 1H), 7.27 (m, 1H), 7.16 (d, 1H, J 8.1 Hz), 7.13 (t, 1H, J 78 Hz), 4.96 (m, 1H), 4.47 (m, 2H), 3.10 (m, 2H), 2.18 (m, 1H), 1.80 (m, 2H), 1.72 (m, 9H), 1.49 (m, 2H). LCMS (pH 3): MH+ 508.8, RT 1.77 minutes.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([O:20][CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+]>O1CCOCC1.Cl>[CH3:21][O:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC1(c2ccccc2)CCNCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
1-t-Butoxycarbonyl-4-methoxy-4-phenylpiperidine (150 mg, 0.51 mmol) was dissolved in a mixed solvent of 1,4-dioxane (20 ml) and concentrated hydrochloric acid (10 ml). The resulting solution was stirred at 0° C. for a while and then gradually returned to a room temperature spending 1.5 hours. The reaction solution was neutralized by adding with sodium hydroxide aqueous solution (1 N), and then the solvent was evaporated under a reduced pressure. The thus obtained residue was mixed with ethyl acetate and water, the reaction product was extracted with ethyl acetate, washed with water and saturated brine and dried with anhydrous sodium sulfate. Then the solvent was evaporated under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 49 mg of the title compound (0.25 mmol, 49% in yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([C:32](=O)[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].[NH2:36][O:37][CH3:38].Cl.CCN(C(C)C)C(C)C>CCO>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([C:32](=[N:36][O:37][CH3:38])[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)=O)c1)NC(=O)c1c(Cl)cccc1Cl
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)=NOC)c1)NC(=O)c1c(Cl)cccc1Cl
Yield: 45.8 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-3-acetyl-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester (0.12 g) in EtOH (5 mL) were added NH2OMe HCl salt (24 mg) and DIEA (60 mg). The mixture was refluxed for 2 h and evaporated. The residue was diluted with EtOAc, washed with 1N HCl, dried, and evaporated. The residue was purified by preparative TLC (silica gel; eluent: EtOAc/hexane 2:1)to give 0.058 g of N-(2,6-dichlorobenzoyl)-3-[1-(methoxyimino)ethyl]-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester. ESMS: m/z 534 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>[Pd].CCO>[F:1][C:2]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCN2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 1-[2-(2-fluoro-4-nitro-phenoxy)-ethyl]-pyrrolidine (1.25 g, 4.92 mmol) and 10% palladium on carbon (0.2 g) in EtOH (20 mL) is stirred for 1 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a brown oil: ESI-MS: 225.1 [MH]+; tR=0.80 min (system 1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68]([C:70]1[N:71]=[C:72]([NH2:75])[S:73][CH:74]=1)=[O:69])[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68]([C:70]1[N:71]=[C:72]([NH:75][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[S:73][CH:74]=1)=[O:69])[CH3:66]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.22 mmol) in methylene chloride (10 mL), HATU (Aldrich, 83 mg, 0.25 mmol) was added followed by the addition of DIPEA (100 uL) and 2-amino-thiazole-4-carboxylic acid ethyl ester (Oakwood, 43 mg, 0.25 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 40-80% EtOAc/hexanes) to give a solid. 32 mg.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:36])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:31]1([CH2:30][O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:37])=[O:3])=[C:8]([CH3:36])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:17]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CCCC3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (80 mg; 0.15 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 43 mg (57%). HPLC-MS: m/z: 495.8 (M)+; Rt: 1.92 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.[BH4-].[Na+].[OH-].[Na+]>CO>[Si:1]([O:8][CH2:9][CH2:10][NH:16][CH2:15][CH:12]1[CH2:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NCC1CC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(tert-Butyldimethylsilyloxy)acetaldehyde (0.98 g) was dissolved in dry methanol (40 ml) and then treated with cyclopropane methylamine (0.634 ml) followed by 4A° molecular sieves (1 g). The resultant mixture was stirred for 5 h at room temperature and then sodium borohydride (0.340 g) was added. After stirring for a further 18 h at room temperature, sodium hydroxide (2N) was added, the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was partitioned between sodium hydroxide (2N) and ethyl acetate. The separated aqueous layer was washed further with ethyl acetate. The combined organic components were dried (over magnesium sulphate), filtered and concentrated under reduced pressure to give the title compound (0.78 g) as a yellow oil.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34])([OH:3])=[O:2].[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C)C=O>[C:35]([O:41][CH2:42][O:2][C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34])=[O:3])(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Reaction time: 48 h

Procedure:
A mixture of 1-carboxymethyl-1,3-dihydro-3-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one (85 mg, 0.20 mmol), pivaloyloxymethylchloride (32 μl, 0.22 mmol) and triethylamine (28 μl, 0.20 mmol) was combined in 2 ml of dry dimethylformamide and allowed to stand at room temperature for 48 hours. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. Extractive work-up gave 100 mg of crude Product which was chromatographed on silica gel (CH3OH-CHCl3, 3:97 v/v elution) to give a white solid after trituration with ether: m.p. 225°-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28](F)[CH:27]=[CH:26][C:21]=4[C:22]([O:24][CH3:25])=[O:23])[C:13]=3[N:12]=[CH:11]2)=[CH:5][CH:4]=1.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28]([N:39]5[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]5)[CH:27]=[CH:26][C:21]=4[C:22]([O:24][CH3:25])=[O:23])[C:13]=3[N:12]=[CH:11]2)=[CH:5][CH:4]=1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc2c1ncn2C(c1ccc(OC)cc1)c1ccc(OC)cc1
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2c1ncn2C(c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
A solution of EXAMPLE 403D (500 mg), and piperazine (420 mg) in dimethylsulfoxide (9 mL) was heated at 100° C. for 3 hours. The crude product was isolated by concentration and, following an aqueous work up, it was purified on silica gel, and was eluted with a 5 and 10% methanol in methylene chloride step gradient to provide the title compound.
Reaction SMILES: [C:1]([O:20]CCCC)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=O)CCCCCCCCCCCCCCCCC.CS(OCCCC)(=O)=O.[OH-].[K+:55]>CS(O)(=O)=O.C(O)CCC>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[K+:55]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCCC
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCOS(C)(=O)=O
Agent: CS(=O)(=O)O
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 50 °C

Procedure:
An esterification reaction mixture (94 g), consisting of butanol (ca., 4.9% w/w), butyl stearate (95.1% w/w), residual stearic acid (trace), residual methanesulfonic acid catalyst (1383 ppm) and undesired butyl methanesulfonate (613 ppm) was treated with 45% aqueous KOH (229 mg, 1.84 mmol as compared to 1.74 mmol MSA originally charged to the reaction). The resulting mixture was heating at 50° C. for 40 minutes. Without wishing to be bound by any particular theory or explanation, it is believed that reaction of butyl stearate with KOH produced potassium stearate, which retains significant solubility in the butyl stearate medium. The formed potassium stearate then reacted with butyl methanesulfonate to produce potassium methanesulfonate and butyl stearate. After filtration of the by-product solid salts (0.6325 g), analysis of the mixture by gas chromatography revealed only 300 ppm unreacted butyl methanesulfonate, a 51% reduction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([N:17]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]([F:16])[F:15])[CH:8]=1)[CH3:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH2:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]([F:16])[F:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(OC(F)F)c1)N=C(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(N)Cc1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
The product from Example 175 Part A (700 mg, 1.65 mmol) was placed in a flask and dissolved in THF (30 mL). 30% (w/v) Citric acid (aqueous solution, 30 mL) was added and the reaction was stirred at rt for 72 h. The solution was extracted with diethyl ether (50 mL), and the aqueous layer was adjusted to a pH 6 using a saturated NaHCO3 solution. The aqueous solution was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered and evaporated to yield 420 mg (97% yield) of a clear glass. MS 260 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2C(=O)C3=CC=CC=C3[C:10]2=[O:19])[N:5]=[C:4]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[CH:3]=1.O.[NH2:30]N>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:30])=[O:19])[N:5]=[C:4]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[CH:3]=1
Reactant: NN
Reactant: NC(N)=Nc1nc(-c2cc(Cl)cc(CN3C(=O)c4ccccc4C3=O)n2)cs1
Solvent: CCO
Solvent: O
Product: NC(=O)NCc1cc(Cl)cc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 32.3 %

Procedure:
A mixture of 4-(4-chloro-6-phthalimidomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.10 g) and hydrazine mono-hydrate (400mg) in ethanol (200 ml) was refluxed for 5 hours. After the solvent and excess hydrazine monohydrate were removed by concentration, water (10 ml) was added to the residue and the suspension was adjusted to pH 2 with 6N-hydrochloric acid. The resulting precipitate was filtered off, washed with water (5 ml) and the filtrate and the washing solution were combined. After the solution was readjusted to pH 4 with aqueous sodium bicarbonate, potassium cyanate (320 mg) was added to the solution and the mixture was stirred for 14 hours at ambient temperature. The reaction mixture was readjusted to pH 4 with 6N-hydrochloric acid, additional potassium cyanate (215 mg) was added and the solution was further stirred for 8 hours. The mixture was made basic to pH 10 with aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of N,N-dimethylformamide and water to give 4-(4-chloro-6-ureidomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.28 g).
Reaction SMILES: [Na].Cl[CH2:3][CH2:4][CH2:5][S:6]([NH:9][C:10]1[N:14]=[C:13]([C@H:15]([CH2:24][CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[O:12][N:11]=1)(=[O:8])=[O:7]>CO>[CH:27]1([CH2:26][CH2:25][CH2:24][C@@H:15]([C:13]2[O:12][N:11]=[C:10]([N:9]3[CH2:3][CH2:4][CH2:5][S:6]3(=[O:8])=[O:7])[N:14]=2)[CH2:16][C:17]([OH:19])=[O:18])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(NS(=O)(=O)CCCCl)no1
Agent: [Na]
Solvent: CO
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(N2CCCS2(=O)=O)no1
Temperature: 25 °C
Reaction time: 72 h
Yield: 105.3 %

Procedure:
Sodium metal (114 mg, 5.00 mmol) was added in portions to MeOH (10 ml) at 0° C. and stirred until all of the sodium had dissloved (˜10 minutes). A solution of tert-butyl (3R)-3-(3-{[(3-chloropropyl)sulfonyl]amino}-1,2,4-oxadiazol-5-yl)-6-cyclohexylhexanoate (preparation 45) (245 mg, 0.50 mmol) in MeOH (3 ml) was added to the reaction mixture and was stirred under a nitrogen atmosphere for 3 days warming to room temperature over this time. The reaction was quenched with H2O and the solvent removed under reduced pressure. The residue was diluted with water and acidified with 2M HCl (pH˜3) and extracted with Et2O followed by EtOAc. The organic extracts were combined, dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (203 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH:4][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Nc1c(F)cc(F)cc1Br
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1c(F)cc(F)cc1Br
Reaction time: 5 h
Yield: 91.7 %

Procedure:
2-Bromo-4,6-difluoroaniline (10.4 g, Aldrich) was dissolved in dichloromethane (75 ml) and treated with pyridine (4.63 g) in an ice bath. 4-Dimethylaminopyridine (0.61 g) was then added and the mixture was allowed to warn to room temperature. After dropwise addition of pivaloyl chloride (7.23 g, BDH), the reaction was stirred for 5 hours. On completion, the mixture was added to diethyl ether (250 ml), washed twice with 2M HCI (250 ml) and the resulting organic layer was treated with saturated NaHCO3 (2×250 ml). The organic layer was washed with water (250 ml), and dried over MgSO4. Removal of the solvent from the filtrate gave the crude title product as a white solid (13.40 g).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Cc1ccc(N)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing p-toluidine as the aniline component. (18%, MS=484.2 (M+H))
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]3=[O:26])[N:9]=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].[ClH:27]>O1CCOCC1>[ClH:27].[O:26]=[C:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[C:8]1[N:9]=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3ccc(C#N)cc3cn2)C(=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2cc(N3CCNCC3=O)ncc2c1

Procedure:
The product of Step B was further treated with 4N HCl in dioxane, and removal of solvent furnished 3-(2-oxopiperazin-1-yl)isoquinoline-7-carbonitrile hydrochloride. The HCl salt was washed with aqueous sodium carbonate, and back extracted with CHCl3-IPA (3:1) to furnish the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15](=[O:18])[CH2:16][NH2:17])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOCC>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH2:16][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:18])[CH:7]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNc1cc(C#N)ccn1

Procedure:
A solution of 2-chloro-4-cyanopyridine (1.00 g, 7.2 mmol), glycine tert-butyl ester (1.5 mL, 10.8 mmol) and DIEA (4.9 mL, 28.9 mmol) in anhydrous DMA (15 mL) was heated at 150° C. for 48 hours. The reaction mixture was diluted with Et2O (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried (MgSO4) and the solvents were removed under reduced pressure. After purification by flash chromatography (silica, DCM), the title compound was obtained as a yellow oil. HPLC (Method A), Rt: 3.1 min (purity: 94%). UPLC/MS, M+(ESI): 178.0 ([M-tBu+2H]+), M−(ESI): 232.1. 1H NMR (DMSO-d6, 300 MHz) δ 8.15 (d, J=5.2 Hz, 1H), 7.44 (t, J=6.2 Hz, 1H), 6.93 (brs, 1H), 6.85 (dd, J=5.2, 1.3 Hz, 1H), 3.94 (d, J=6.2 Hz, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH:1]1([CH:4]=[C:5]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:8][N:7]3[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=[C:6]23)[CH2:3][CH2:2]1>[Pd].C(O)C>[C:14]([O:13][C:11]([N:10]1[CH2:9][CH2:8][N:7]2[N:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[N:20]=[C:6]2[CH:5]1[CH2:4][CH:1]1[CH2:2][CH2:3]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1=CC1CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1CC1CC1
Reaction time: 8 h

Procedure:
A mixture of 50 mg (0.15 mmol) of tert-butyl 8-(cyclopropylmethylene)-2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5-α]pyrazine-7(8H)-carboxylate and 25 mg of 10% palladium on carbon in 0.5 mL of ethanol was stirred under an atmosphere of hydrogen overnight. The mixture was filtered and the filtrate concentrated to give the title compound.