Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:61][C:58]2[S:59][C:60]3[C:52]([CH:47]4[CH2:48][O:49][CH2:50][CH2:51][O:46]4)=[CH:53][CH:54]=[C:55]([O:62][CH3:63])[C:56]=3[N:57]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(N(C)C)cc3)nc12

Procedure:
From 4-dimethylaminobenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+22.6° (c=0.45, CHCl3), ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:16])[CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]([N+:17]([O-])=O)[CH:4]=1)#[CH:2].CCO.Cl>[Fe].C1COCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][CH2:10][N:9]([CH3:16])[C:6]1[C:5]([NH2:17])=[CH:4][C:3]([C:1]#[CH:2])=[CH:8][CH:7]=1
Reactant: C#Cc1ccc(N(C)CCCN(C)C)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: C#Cc1ccc(N(C)CCCN(C)C)c(N)c1
Temperature: 90 °C

Procedure:
To N-(4-ethynyl-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (730 mg, 2.79 mmol), EtOH (40 mL) and THF (13 mL) was added concentrated HCl (1.0 mL) and iron metal (10.6 g, 191 mmol). A reflux condenser was attached and the mixture was heated overnight at 90° C. The cooled mixture was filtered through a pad of Celite, concentrated and purified by flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to yield N1-(3-dimethylamino-propyl)-4-ethynyl-N1-methyl-benzene-1,2-diamine. MS m/z=232 [M+1]+. Calc'd for C14H21N3: 231.34.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]1[C:12](=[O:36])[N:13]([CH2:22][C:23]([NH:25][CH:26]([CH:33]([CH3:35])[CH3:34])[CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:24])[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:8]2=1)#[N:2].Cl.CN(C)CCCN=C=NCC.ClC(Cl)C(O)=O.C(OCC)(=O)C>CS(C)=O.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]1[C:12](=[O:36])[N:13]([CH2:22][C:23]([NH:25][CH:26]([CH:33]([CH3:34])[CH3:35])[C:27](=[O:32])[C:28]([F:30])([F:29])[F:31])=[O:24])[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:8]2=1)#[N:2]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)cc2c([nH]c3c(C#N)cccc32)c1=O)C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)cc2c([nH]c3c(C#N)cccc32)c1=O)C(=O)C(F)(F)F
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 2-(8-cyano-1-oxo-3-phenyl-1,2-dihydropyrido[3,4-b]indol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (0.3 g) in dimethyl sulfoxide (2 mL) and toluene (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.4 g) and dichloroacetic acid (0.23 mL), and the resulting solution was allowed to stir for 2 hours. The mixture was poured into ethyl acetate and was washed (1N hydrochloric acid, H2O), dried, and evaporated. The resulting material was chromatographed, with methanol:dichloromethane (3:97) as the eluent, to give the title compound (0.23 g) as a yellow solid; TLC: Rf =0.5, methanol:dichloromethane (5:95);
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[O:16][C@@H:12]([CH2:13][CH2:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:28]=[CH:27][C:24]=1[CH:25]=O.C([O-])(=O)C.[NH4+]>CCO>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[O:16][C@@H:12]([CH2:13][CH2:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:30][C:23]=3[O:22][CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2CC[C@@H]1O2
Reactant: COc1cc(N2CCOCC2)ccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(N2CCOCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4CC[C@H]3O4)c(Cl)cnc2[nH]1
Temperature: 70 °C

Procedure:
(1S,2R,3S,4R)-3-(2,3-diamino-5-chloropyridin-4-ylamino)-7-oxabicyclo[2.2.1]heptane-2-carboxamide (17) (140 mg, 0.47 mmol), 2-methoxy-4-morpholinobenzaldehyde (93 mg, 0.42 mmol) were taken in EtOH (15 ml) to which ammonium acetate (40 mg) was added and the reaction mixture was heated at 70° C. for 48 h. Crude LCMS showed the desired product along with trace of starting material. The reaction mixture was allowed to come to rt and the precipitated was filtered and washed well with hot ethanol to afford the desired product (120 mg, 51%) as an off white solid. NMR: δ (1H, 400M Hz, CDCl3): 1.50-1.80 (4H, m), 2.95 (1H, d, J=8.4 Hz), 3.27 (4H, bs), 3.76 (4H, bs), 3.96 (3H, s), 4.32 (1H, d, J=4.4 Hz), 4.57 (1H, s), 5.51 (1H, t, J=4.4 Hz), 6.63 (1H, s), 6.69 (1H, d, J=8.4 Hz), 6.90 (1H, d, J=8.4 Hz), 7.18 (1H, s), 7.60 (1H, s), 7.91 (1H, s), 8.05 (1H, d, J=8.8 Hz), 12.14 (1H, s). LCMS (254 nm): [M+H]+ 499.00 (100%). HPLC: (254 nm) 97.68%.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH:10]([NH:27]C(OCC2C=CC=CC=2)=O)[C:9]1=[O:38])=[O:6])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:11][CH:10]([NH2:27])[C:9]1=[O:38])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)OCc1ccccc1)CN2c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2c1ccccc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
1-tert-Butylcarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.11 g) was dissolved in methanol (20 ml), 10% palladium carbon (220 mg) was added, and the mixture was stirred for 2 hours under hydrogen atmosphere. Palladium carbon was removed by filtration, the filtrate was concentrated under reduced pressure, to thereby obtain 0.82 g of the titled compound as colorless amorphous(Yield: 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[NH:19][C:18]1=[O:30]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[NH:19][C:18]1=[O:30])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: COc1ccc2c(c1)NC(=O)C(N)CC2
Product: COc1ccc2c(c1)NC(=O)C(NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CC2

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step D by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.44 (s,6H), 1.50 (s,9H), 1.80 (m,1H), 2.80 (m,5H), 3.86 (s,3H), 4.62 (m,1H), 6.62 (d,2 Hz,1H), 6.76 (dd;2,8 Hz;1H), 7.20 (d,8 Hz,1H). FAB-MS: calculated for C21H31N3O5 405; found 406 (M+H, 42%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[S:23]1[CH:27]=[C:26]([CH2:28][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:25]=[CH:24]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[CH:28]\[C:26]2[N:25]=[CH:24][S:23][CH:27]=2)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C(=C\c1cn(-c2ccccc2)nc1OCc1ccccc1)\c1cscn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.3 %

Procedure:
A mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.70 g), [(1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (3.64 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:3, v/v) to give 4-{(Z)-2-[3-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a colorless oil (0.82 g, yield 37%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19]CCCC)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)nn1
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
A solution of butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 3) (0.36 g, 1.0 mmol) in THF (4 ml) and methanol (4 ml) was treated with aqueous sodium hydroxide 1N (4 ml) and allowed to stand at ambient temperature for 1.5 hours. The reaction was evaporated to a small volume, diluted with water and acidified with acetic acid. After standing for 18 hours, the precipitate was filtered, washed with water and ether, and dried (MgSO4) to give the title compound as a white solid (0.26 g, 71%).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[CH2:40][CH2:39][NH:38][C:37]2=[O:41])[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[C:15]1([CH2:14][N:38]2[CH2:39][CH2:40][N:36]([C:28]3[S:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:26]([CH3:25])[N:27]=3)[C:37]2=[O:41])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1
Reactant: BrCc1nccc2ccccc12
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3nccc4ccccc34)C2=O)nc1C
Yield: 85 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)isoquinoline to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 85% yield: MS (ES+) m/z 397.2 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][N:13]([CH3:19])[C:12]=3[N:11]=[C:10]2S)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:23]>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][N:13]([CH3:19])[C:12]=3[N:11]=[C:10]2[Cl:23])=[CH:5][CH:4]=1
Reactant: Cn1cnc2c(=O)n(-c3ccc(Br)cc3)c(S)nc21
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: Cn1cnc2c(=O)n(-c3ccc(Br)cc3)c(Cl)nc21
Temperature: 135 °C

Procedure:
1-(4-Bromophenyl)-2-mercapto-9-methyl-1,9-dihydro-6H-purin-6-one hydrochloride (2.05 g, 5.49 mmol) is added to POCl3 (87 mL) and the resulting solution is refluxed at 135° C. for 38 h. Most volatiles are removed under vacuum and the residual solvents are co-evaporated with toluene (50 mL×3). The resulting dark solid is dissolved in CH2Cl2 (300 mL), washed with saturated NaHCO3 solution (100 mL×5), brine (50 mL×2), and dried over MgSO4. After removing solvent in vacuo, silica gel column chromatography (EtOAc:hexanes=50:50) gives the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) 7.51 (1H, s), 7.67 (2H, d), 7; 14 (2H, d), 3.83 (3H, s); m/z (ES+) 340.90 (M+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[C:29]([N+:34]([O-:36])=[O:35])[CH:30]=[N:31]2)=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.O>[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[C:29]([N+:34]([O-:36])=[O:35])[C:30]([NH:7][CH2:6][CH2:5][CH2:4][CH:3]([O:8][CH3:9])[O:2][CH3:1])=[N:31]2)=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: COC(CCCN)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(CCCNc1nc2cc(Br)ccc2cc1[N+](=O)[O-])OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
4-Aminobutyraldehyde dimethylacetal (29.41 g, 208.6 mmol), triethylamine (36.36 mL), and potassium carbonate (24.0 g, 173.9 mmol) were added sequentially to a solution of 7-bromo-4-chloro-3-nitroquinoline (50.1 g, 173.9 mmol) in chloroform (200 mL) cooled to 0° C. The reaction was allowed to warm to ambient temperature and was stirred for 4 hours. The reaction mixture was then diluted with water (100 mL) and the reaction was stirred for 10 minutes and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 66.9 g of (7-bromo-3-nitroquinolin-yl)(4,4-dimethoxybutyl)amine as a yellow solid.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:49])[C@@H:14]([NH:30][C:31](=[O:48])[C@@H:32]([NH:36][C:37](=[O:47])[C@H:38]([CH3:46])[C@H:39]([O:44][CH3:45])[CH2:40][CH2:41][CH:42]=[CH2:43])[CH:33]([CH3:35])[CH3:34])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:17]=2)[NH:8]1)=[O:6].C([O-])(=O)C.[NH4+]>O1CCCC1.O.[Zn]>[C:26]([Si:23]([CH3:25])([CH3:24])[O:22][C:18]1[CH:17]=[C:16]([CH2:15][C@H:14]([NH:30][C:31](=[O:48])[C@@H:32]([NH:36][C:37](=[O:47])[C@H:38]([CH3:46])[C@H:39]([O:44][CH3:45])[CH2:40][CH2:41][CH:42]=[CH2:43])[CH:33]([CH3:34])[CH3:35])[C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]2)=[O:49])[CH:21]=[CH:20][CH:19]=1)([CH3:28])([CH3:27])[CH3:29]
Reactant: C=CCC[C@@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1)C(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC[C@@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)O)N1)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.3 %

Procedure:
To a solution of (S)-1-{(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-[(S)-2-((2R,3R)-3-methoxy-2-methyl-hept-6-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (560 mg, 0.71 mmol) in tetrahydrofuran (16 mL) was added zinc dust (1.0 g, 15.6 mmol) followed by a solution of ammonium acetate (817 mg, 10.6 mmol) in water (7 mL). The reaction mixture was stirred vigorously at room temperature for 24 hours. The reaction mixture was filtered through celite and the filter pad was washed with dichloromethane. The aqueous layer was acidified to pH 4-5 with 2 M hydrochloric acid and the mixture was extracted with dichloromethane. The organic layers were combined and dried by passing through a hydrophobic frit. The solvent was evaporated and dried to afford (S)-1-{(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-[(S)-2-((2R,3R)-3-methoxy-2-methyl-hept-6-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (480 mg) which was used crude in the next step. LCMS (m/z) 661 [M+H], Tr=5.46 min.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]2=[N:3][C:2]=1[C:15]([O:17]C)=[O:16].CO.O.[OH-].[Li+]>C1COCC1>[N:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]2=[N:3][C:2]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1nc2n(n1)-c1ccccc1OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nc2n(n1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ester 86 (0.166 g, 0.677 mmol) was dissolved in 3:2:1 THF:MeOH:H2O (31.2 mL), treated with 4 N aqueous lithium hydroxide (1.32 mL), and the mixture was stirred for 30 min at 25° C. (FIG. 18). The reaction was quenched with 1 N aq. HCl (20 mL) and the solution was extracted three times with 20 mL EtOAc. The combined organic extracts were dried with sodium sulfate, and concentrated to give crude 4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylic acid which was taken forward to the next step. LRMS m/z Calcd. for C12H9N3O3: 231.06439. found: 232.1 [M+1].
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:11][CH3:10])[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ccnc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(Cl)c1N

Procedure:
To a stirred solution of 2-bromo-4-chloropyridin-3-amine (prepared as described in US2002/0119982) (1.0 eq.) in dry MeOH (0.25M) under argon was added a solution of NaOMe (25% wt in MeOH, 1.5 eq.) and the reaction mixture was refluxed for 1 h, more NaOMe (25% wt in MeOH, 1.5 eq) was added and the reaction mixture was refluxed for an additional 2 h. The volatiles were removed under reduced pressure and the crude product was purified by flash chromatography eluting with 2-10% EtOAc/petroleum ether affording the titled compound as yellow oil. 1H-NMR (300 MHz, DMSO-d6, 300K) δ 7.33 (1H, d, J=5.5 Hz), 6.88 (1H, d, J=5.5 Hz), 5.13 (2H, bs), 3.89 (3H, s). MS (ES) C6H7ClN2O requires: 158, found: 159, 161 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.O.O.O.C([O-])(=O)C.[Na+].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+].[OH-].[Na+].CC(O)C.[ClH:37]>O.C(OCC)(=O)C.CO.C(O)(=O)C>[ClH:37].[CH2:21]([NH:28][C@H:10]([CH3:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: NCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C[C@@H](C)NCc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
4-Methoxy phenyl acetone (50 kg, 0.305 M), sodium acetate trihydrate (62 kg, 0.455 M) were charged in to the reactor containing acetic acid (170 kg,) and methanol (160 lit). The reaction mass was chilled to 0-5° C. Benzylamine (36 kg, 0.336 M) was added slowly into the reactor maintaining temperature between 0-5° C. After stirring for two hours at 0-5° C., the reaction mass was treated with sodium borohydride (25 kg, 0.657 M) maintaining temperature below 10° C. and was stirred further for 2 hours. The reaction mass was diluted with water (500 lit) and treated with a solution of sodium hydroxide (70 kg sodium hydroxide in 150 lit water) below 30° C. The reaction mass was extracted with methylene chloride twice (200 lit), washed with water and concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 lit), cooled to 10-15° C. and the pH of reaction mass was adjusted to 1-2 with IPA+HCl. The solids were isolated by filtration, dried to yield title compound as hydrochloride salt. (50 Kg, 56.5%)
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][N:36]([CH3:41])[CH3:35])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CN(C)CC(=O)O
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 16.2 %

Procedure:
4-{5-[2-Amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 459 mg, 1 mmol), N,N-dimethylglycine (206 mg, 2 mmol), and triethylamine (0.278 mL, 2 mmol) were stirred in dry DMF (5 mL) and then HATU (760 mg, 2 mmol) was added portionwise. The reaction mixture was heated at 70° C. for 40 mins then a further quantity of HATU (760 mg, 2 mmol) was added and the mixture heated at 80° C. for 1 hr. The reaction mixture was allowed to cool and then partitioned between EtOAc and water. The organic layer was washed with water followed by brine, and then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was treated with DCM, the suspension filtered and the filtrate purified by flash chromatography with a gradient of 0-10% MeOH in DCM to afford the title compound as a white solid (88 mg).
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([O:24]C)[CH:21]=[C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:19]=2)=[C:14]([F:33])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].C(S)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([OH:24])[CH:21]=[C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:19]=2)=[C:14]([F:33])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: COc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(O)cc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To a solution of isopropyl 2-[2,4-difluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenoxy]acetate (II(q)) (700 mg, 1.52 mmol, 1.0 eq) in DCM (20 mL) at 0° C. was added AlCl3 (1.2 g, 9.12 mmol, 6.0 eq) and ethanethiol (566 mg, 9.12 mmol, 6.0 eq) under N2. The reaction mixture was stirred at room temperature for 3 h and the resulting mixture was poured into aqueous NaHCO3 and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:20) to give the title compound as a yellow oil (500 mg, 74%).