Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][CH2:41][C:42]#[N:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:53][OH:54]>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:22]([CH2:40][CH2:41][C:42](=[NH:43])[NH:53][OH:54])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCC#N)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCC(=N)NO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 80 °C
Reaction time: 31.5 h
Yield: 56.5 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-cyanoethyl)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (500 mg) is dissolved in ethanol (5 ml), and thereto are added sodium carbonate (292 mg) and hydroxylamine hydrochloride (192 mg). The mixture is heated at 80° C. and stirred for 31.5 hours. The reaction solution is cooled to room temperature, and partitioned by adding water and ethyl acetate. The organic layer is washed with saturated brine, then dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(N-hydroxycarbamimidoyl)ethyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (297 mg) MS (m/z): 670 [M+H]+, and (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carbamoylethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (140 mg) MS (m/z): 655 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: OC(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F

Procedure:
43.15 g (0.157 mol) of 2-(2,2,2-trifluoroethoxy)-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 2.66 g (0.0078 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 400 ml of ethyl acetate at room temperature. 240 ml (0.235 mol) of an approximately 6% strength sodium hypochlorite solution are metered in within 1 hour with vigorous stirring and the mixture is stirred for a further 2 hours during which the reaction temperature rises to 40° C. The reaction mixture is added to 500 ml of water, the phases are separated, the aqueous phase is extracted several times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product (27 torr, 100°-102° C.), 24.47 g (57% of theory) of 2-(2,2,2-trifluoroethoxy)-5-trifluoroacetylpyridine are obtained, which, according to GC, is 97% pure.
Reaction SMILES: CS(C)=O.C(N(CC)CC)C.[OH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:40][CH2:39][C:25]2([O:30][CH2:29][CH2:28][N:27]([C:31]([C:33]3[N:34]=[C:35]([CH3:38])[S:36][CH:37]=3)=[O:32])[CH2:26]2)[CH2:24][CH2:23]1.S(=O)(=O)=O.N1C=CC=CC=1>ClCCl.[Cl-].[Na+].O>[CH3:38][C:35]1[S:36][CH:37]=[C:33]([C:31]([N:27]2[CH2:26][C:25]3([CH2:39][CH2:40][N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[O:12])[CH2:23][CH2:24]3)[O:30][CH2:29][CH2:28]2)=[O:32])[N:34]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)cs1
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCCCCCCC=O)CC3)C2)cs1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
DMSO (0.32 mL) and triethylamine (0.32 mL) were added to a solution of (9-(9-hydroxynonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (example 2, step a) (0.32 g) in dichloromethane (5 mL). The mixture was cooled in an ice-salt bath and pyridine sulphur trioxide (0.36 g) was added. The reaction was stirred at −10° C. for 1 h then allowed to warm to room temperature and stirred for a further 3 h. The reaction was diluted with DCM (20 mL) then poured into brine (20 mL). The layers were separated and the organic layer washed with brine (20 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine to gradient to give the subtitled compound as a yellow oil. Yield 0.25 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24](O)=[O:25])[NH:13][C:12]43[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:35][C@H:36]4[CH2:37][CH2:38][C@H:39]([C:42](=[O:43])[N:44]([CH3:45])[CH3:46])[CH2:40][CH2:41]4)=[O:25])[NH:13][C:12]43[CH2:27][CH2:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH2:31]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](N)CC1
Reactant: CC1(C)CCC2(CC1)N[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Agent: Cl
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)[C@@H]2NC3(CCC(C)(C)CC3)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2ccnc(Cl)c2F)CC1

Procedure:
The compound (29 mg, 0.06 mmol) obtained in Step 1 of Example 17 and trans-4-amino-N,N-dimethylcyclohexanecarboxamide hydrochloride (WO2008/068171) (17 mg, 0.08 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 12 to give 36 mg (100%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13].[C:15](=O)([O-:17])[O-:16].C[Mg+2].Cl.C(OCC)C>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]([C:15]([OH:17])=[O:16])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1(=[O:13])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)Cc2ccccc2S1(=O)=O
Agent: C[Mg+2]
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C(=O)C(C(=O)O)c2ccccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
In a four neck flask equipped with reflux condenser, stirrer, thermometer and calcium drying tube, 1.06 g (0.005 mole) 3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine 1,1-dioxide and 2.6 g (0.02 mole) methylmagnesiumcarbonate in 20 ml N,N-dimethylformamide were added. The mixture was stirred at 90°-100° C. for 3 hours. The resulting solution was poured quickly into a mixture of 30 ml conc-hydrochloric acid, 70 g ice chips and 200 ml diethylether. After stirring the mixture for 10 minutes, the separated diethylether layer was evaporated in vacuo to obtain 1.25 g of 3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxylic acid 1,1-dioxide. The obtained compound was dissolved in 20 ml benzene and to the solution, 1.3 ml thionyl chloride and 0.4 ml N,N-dimethylformamide were added.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[C:15]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:20]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:15]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:25][CH:26]=3)[N:20]=2)=[CH:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:39])=[CH:13][CH:12]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C=C(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(C=C(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
3-(4-{2-(4-Chlorophenyl)-2-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]vinyl}benzoylamino)propionic acid methyl ester (14 mg) was dissolved in methanol (5 mL) and 1 N sodium hydroxide (72 μL, 3 equivalents) and 5 drops THF were added and the resulting mixture was stirred at room temperature for 1 hour. More 1 N sodium hydroxide (72 μL, 3 equivalents) and 5 drops THF were added and the resulting mixture was stirred at room temperature for 1 hour and at 50° C. for 1 hour. The mixture was concentrated in vacuo and the residue was added water (5 mL) and 1 N hydrochloric acid was added to pH 2. The solid was filtered off, washed with water and dried in vacuo to afford 6 mg (4%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:29][CH3:30])=[C:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1.[C:42]([O:46]CC)(=[O:45])[CH:43]=[CH2:44].[OH-].[Na+].Cl>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:29][CH3:30])=[C:19]([CH:23]4[CH2:28][CH2:27][N:26]([CH2:44][CH2:43][C:42]([OH:46])=[O:45])[CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: C=CC(=O)OCC
Reactant: CCc1c(-c2nnc(-c3ccc(OC(C)C)c(Cl)c3)s2)cccc1C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1c(-c2nnc(-c3ccc(OC(C)C)c(Cl)c3)s2)cccc1C1CCN(CCC(=O)O)CC1
Temperature: 60 °C
Yield: 5.2 %

Procedure:
To a solution of 4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]piperidine (D120) (200 mg, 0.452 mmol) in Acetonitrile (10 mL) was added DBU (0.205 mL, 1.357 mmol) and ethyl 2-propenoate (136 mg, 1.357 mmol). The reaction solution was heated to 60° C. for 2 h. The reaction solution was concentrated and the residue was hydrolized with a solution of NaOH (4.52 mL, 2.262 mmol) in water. The reaction mixture was neutralized with 2N HCl till pH ˜6.0. The mixture was extracted with EA/THF for 3 times. The combined organic layers were concentrated and purified by Mass Directed AutoPrep to afford 3-{4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]-1-piperidinyl}propanoic acid (E95) (12 mg) as a TFA salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]=2[CH:9]=1.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(=O)O)C(=O)NC3=O
Agent: Cl
Agent: c1cc[nH+]cc1
Product: O=C(O)CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Yield: 50 %

Procedure:
Demethylation of (116) prepared as described in example 229 with pyridinium hydrochloride using the procedure described in example 81 gave (117) (50%) as a yellow powder, mp 286° C. 1H NMR δ [(CD3)2SO] 12.40 (br, 1H), 11.06 (br s, 1H), 9.37 (br s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.81 (s, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.57 (m, 1H), 7.53–7.43 (m, 3H), 7.13 (dd, J=8.7, 2.4 Hz, 1H), 4.67 (t, J=6.8 Hz, 2H), 2.74 (t, J=6.8 Hz, 2H). Found: C, 60.00; H, 3.65; N, 5.52. C23H15ClN2O5.1.5H2O requires C, 59.81; H, 3.92; N, 6.06.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:21][C:22]([OH:39])([CH3:38])[CH2:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:27]4[CH:26]=[N:25][N:24]([CH2:23][C:22]([OH:39])([CH3:38])[CH3:21])[CH:28]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(Br)cc2-3)cn1

Procedure:
10-bromo-9-fluoro-3-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propan-2-ol similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[e]imidazo[1,2-a]azepine-2-carboxamide to produce crude 10-bromo-9-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo [1,2-d][1,4]oxazepine-2-carboxamide. This intermediate was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 25 mg (27%) of 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-3-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[CH2:36]([NH:40][CH3:41])[CH:37]([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:36]([N:40]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1)[CH3:41])[CH:37]([CH3:39])[CH3:38]
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Reactant: CNCC(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CN(C)CC(C)C)c3)c1)=N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A stirred suspension of 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 283) (213 mg, 0.50 mmol) and thionyl chloride (0.11 ml, 1.50 mmol) in CH2Cl2 was refluxed for 45 min, evaporated to dryness and dissolved in DMF (3 ml). To the stirred solution N-isobutyl-methyl-amine (436 mg, 5.0 mmol) was added and the reaction mixture was stirred at RT for 1 h. Aqueous work-up (CH2Cl2) and further purification by column chromatography on silica gel (CH2Cl2/MeOH 15:1) yielded the title compound as a light yellow solid (142 mg, 57%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12](=O)[CH3:13])=[N:9][N:8]=2)[CH:2]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12](=[N:16][OH:17])[CH3:13])=[N:9][N:8]=2)[CH:2]=1
Reactant: CC(=O)c1nnc(-c2cccnc2)s1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=NO)c1nnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]ethanone (1.0 g, 4.68 mmol, prepared according to WO 2010/006713) in 50 ml EtOH was treated with hydroxylamine hydrochloride (0.345 g, 4.91 mmol) and potassium carbonate (0.686 g, 4.91 mmol), and stirred at room temperature, monitored by LCMS and TLC. After 3 hours, the mixture was concentrated in vacuo to approximately 10 ml. Addition of saturated ammonium chloride gave a precipitate which was filtered, and washed successively with water, isopropanol, and tertiary-butyl methyl ether. This yielded 1-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]ethanone oxime (577 mg, 51%) as a 5:1 mixture of isomers.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[S:22][CH:21]=[C:20]([C:23]5[CH:33]=[CH:32][C:26]([C:27](OCC)=[O:28])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[S:22][CH:21]=[C:20]([C:23]5[CH:33]=[CH:32][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1ccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Ethyl 4-(2-(6-morpholinopyridin-3-ylamino)thieno[3,2-d]pyrimidin-7-yl)benzoate (150 mg, 0.33 mmol) was dissolved in anhydrous tetrahydrofuran (1.5 mL) and lithium aluminum hydride 2.0 M tetrahydrofuran (0.25 mL, 0.50 mmol) solution was slowly added at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was diluted with ethyl ether (2.0 mL). The remaining lithium aluminum hydride was removed by adding water very slowly. After adding magnesium sulfate, the mixture was concentrated by filtering. The resultant target compound (130 mg, 95% yield) was used in the following reaction without purification.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:9]=[CH:8]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26]Cl>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][N:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:9]=[CH:8]1
Reactant: CCOC(=O)c1nc[nH]c1C(=O)OCC
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(Cc2ccc(Cl)c(Cl)c2)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Potassium t-butoxide (10.9 g) was added with stirring to a solution of diethyl imidazole-4,5-dicarboxylate (20 g, described by Jones, J.A.C.S. 74, 1085 (1952)) in dry dimethylformamide (300 ml) at room temperature and the mixture was stirred for 40 minutes. 3,4-Dichlorobenzyl chloride (20.4 g) was added and the mixture was heated at reflux for 11 hours. The cooled reaction mixture was poured into ice-water (500 ml) and extracted with chloroform (2×200 ml). The combined extracts were washed with water (3×300 ml), dried over magnesium sulphate, filtered and evaporated to dryness. The solid residue was crystallised from methanol (100 ml) to give diethyl 1-(3,4-dichlorobenzyl)imidazole-4,5-dicarboxylate, m.p. 105°-107° C., (13 g) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1F.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCOCC2)c(Br)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 77.2 %

Procedure:
1-Bromo-2-fluoro-4-methyl-5-nitrobenzene (1.0 g, 4.3 mmol) [Aldrich] was stirred in N,N-dimethylformamide (10 mL) with potassium carbonate (1.5 g, 11.0 mmol), and morpholine (0.56 mL, 6.4 mmol) was added. The mixture was stirred for 3 hours and diluted with saturated sodium bicarbonate solution. Extraction with ethyl acetate gave the desired compound (1.0 g, 77%). LCMS for C11H14BrN2O3 (M+H)+: m/z=301.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]([F:25])[F:24])[CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]([F:25])[F:24])[CH:16]=3)[CH3:28])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: FC(F)COc1cccc(CNCCc2c[nH]c3cc(Cl)ccc23)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: CN(CCc1c[nH]c2cc(Cl)ccc12)Cc1cccc(OCC(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine N-(2-(6-chloro-1H-indol-3-yl)ethyl)-3-(2,2-difluoroethoxy)benzylamine (276 mg, 0.76 mmol) and formaldehyde (55.5 μL of a 38% aqueous solution, 0.76 mmol) in dichloroethane (15 mL) and stir at room temperature for 10 minutes; then add in two portions over 10 minutes sodium triacetoxyborohydride (321 mg, 1.51 mmol). Stir the reaction mixture at room temperature overnight and dilute with methanol (10 mL) and quench with one drop of glacial acetic acid. Remove the solvent in vacuo, to give a residue, redissolve the crude residue in methanol and directly load onto a 10 g SCX column. After washing the column thoroughly with methanol, elute with 2 N ammonia in methanol. Concentrate in vacuo to give the title compound as an oil. Dissolve the oil (239 mg, 0.64 mmol) in methanol (20 mL) and treat with a solution of ammonium chloride (36 mg, 0.67 mmol) in methanol (5 mL). Sonicate the mixture for 10 minutes before removal of the solvent in vacuo to give the title compound as the hydrochloride salt Dissolve the salt in 10 mL of 1:1 acetonitrile-water and lyophilize overnight, providing a fluffy white solid. Triturate the solid with diethyl ether (10 mL) and acetonitrile (2 drops), filter, and dry to give the title compound as the hydrochloride salt: mp: 63.8-65.8° C.; 1H NMR (400 MHz, dmso-d6): 11.10 (br s, 1H), 7.52 (d, 1H, J=8.4 Hz) 7.36 (d, 1H, J=2.0 Hz), 7.40-7.26 (m, 2H), 7.22 (d, 1H, J=2.4 Hz), 7.20-7.11 (m, 1H), 7.04 (br d, 1H, J=7.6 Hz), 6.96 (dd, 1H, J=8.6, 1.4 Hz), 6.38 (tt, 1H, J=54.4, 3.6, Hz), 4.50-4.02 (br m, 2H), 4.30 (td, 2H, J=14.4, 3.2 Hz), 3.15 (br s, 4H), 2.68 (br s, 3H); MS (ES+): m/e 378.9 (M+1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].Cl>C(O)C>[Cl:11][CH2:10][CH:12]([OH:14])[CH2:13][NH:4][C:3]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=1[Cl:1]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: ClCC1CO1
Agent: Cl
Solvent: CCO
Product: OC(CCl)CNc1ccc(Cl)cc1Cl
Reaction time: 288 h
Yield: 41.1 %

Procedure:
324.0 Grams (2.0 mol) of 2,4-dichloroaniline, 400 ml absolute ethanol, 185.1 g (2.0 mol) of epichlorohydrin and 3 g of conc. hydrochloric acid are added together in this sequence with stirring and then allowed to stand for 12 days. The solution is thereafter concentrated in vacuum to a brown oily residue which is distilled in high vacuum. The main fraction, which boils between 130° C. and 153° C./0.01 Torr, is collected and redistilled, yielding 209 g of N-(3-chloro-2-hydroxypropyl)-2,4-dichloroaniline as a clear liquid, boiling at 142°-145° C./0.01 Torr.