Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH:15]=1.CCN(CC)CC>CN(C=O)C>[N+:11]([C:5]1[C:6]([S:8][C:9]#[N:10])=[N:7][C:2]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)=[N:3][CH:4]=1)([O-:13])=[O:12]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: c1ccc2[nH]cnc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CSc1nc(-n2cnc3ccccc32)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A mixture of 2-chloro-5-nitro-4-thiocyanatopyrimidine (5.0 g, 23 mmol, WO 2003/032994) and benzimidazole (2.72 g, 23 mmol) in 200 mL of DMF was cooled to 0 C and Et3N (2.33 g, 23 mmol) was added. The ice-bath was removed and the contents were stirred for 3 h at RT. The reaction mixture was diluted with water and filtered. The solid was washed with water, followed by ice-cold methanol and dried in vacuo to provide 3.1 g of 1-(5-nitro-4-thiocyanatopyrimidin-2-yl)benzimidazole. 1H NMR (300 MHz, DMSO-d6) □□ 9.70 (s, 1H), 9.15 (s, 1H), 8.90-8.80 (m, 1H), 7.95-7.80 (m, 1H), 7.55-7.35 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22](O)([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[FH:40].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([F:40])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: F
Reactant: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 42 °C
Reaction time: 9 h

Procedure:
To a solution of 186 mg (0.368 mmol) of 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile in 3 mL of CH2Cl2 1 mL of hydrogen fluoride-pyridine was added and it was stirred for 9 h at 42° C. Then the reaction mixture was poured to 7 mL of 5N NaOH, 7 mL of ag NaHCO3 and 30 mL of CH2Cl2. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid; 1NMR (CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.24 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 8H); Mass Spectrum: m/e=478 (M+1 35Cl, 35Cl) and 480 (+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9](=[O:29])[C@@H:10]([N:18]([CH2:26][CH:27]=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:30])[C:9](=[O:29])[C@@H:10]([N:18]([CH2:26][CH2:27][OH:28])[C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CC=O)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CCO)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
Combine (S)-N-benzyl-N-methyl-2-[N-(t-butoxycarbonyl)-2-oxo-ethylamino]-3-phenyl-propionamide (5.0 mmol) and sodium borohydride (5.0 mmol) in ethanol (20 mL). Stir for 16 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with 0.5M hydrochloric acid solution and water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([N:16]=[C:17](SC)[NH:18]C(OC(C)(C)C)=O)=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[CH:31]([NH:34][NH2:35])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:34]([CH:31]([CH3:33])[CH3:32])[N:35]=[C:17]([NH2:18])[N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(C)NN
Reactant: CSC(=NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 120 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a mixture of methyl N′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate (1.2 g, 2.5 mmol) and isopropylhydrazine hydrochloride (0.55 g, 5 mmol) in DMF (50 mL), DIPEA (3.2 g, 25 mmol) was added. The resulting mixture was stirred at 120° C. overnight. The reaction mixture was concentrated, and MeOH (30 mL) was added. The solid was collected to give 5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine (430 mg, 49%). 1H NMR (DMSO, 400 MHz) δ 8.28 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.26 (s, 1H), 5.69-5.66 (m, 1H), 5.35 (s, 1H), 4.49 (s, 4H), 4.10 (s, 1H), 3.14 (s, 2H), 1.37 (d, J=6.8 Hz, 6H)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12]Br.[CH3:14][Si:15]([CH3:31])([CH3:30])[CH2:16][CH2:17][O:18][CH2:19][N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH2:22][C:21]1=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[N+:9]([C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][C:22]1([C:23]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:20]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:30])([CH3:14])[CH3:31])[C:21]1=[O:29])[CH2:12]2)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene from Step E (40.9 g, 132 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one from Step C (31.5 g, 119 mmol) in DMF (2 L) was added cesium carbonate (129 g, 397 mmol), portionwise, over 5 min. After 18 h, acetic acid (7.6 mL) was added and the mixture was concentrated to a volume of about 500 mL, then partitioned between EtOAc (1.5 L) and H2O (1 L). The organic layer was washed with H2O (1 L), then brine (500 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=412 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19]C)=[O:18].[Cl:21][C:22]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:23]=1[CH:24]=[CH:25][C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:26](=[O:27])/[CH:25]=[CH:24]/[C:23]3[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:22]=3[Cl:21])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)C=Cc1cccc(Cl)c1Cl
Product: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3cccc(Cl)c3Cl)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared employing a procedure analogous to that described in Example 1 using methyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and 2,3-dichlorocinnamic acid followed by a procedure analogous to that described in Example 2. LC-MS Method 1 tR=1.98, min, m/z=480; 1H NMR (CDCl3) 1.52 (d, 2H), 1.71 (m, 2H), 2.40 (m, 1H), 2.49 (m, 1H), 2.65-3.10 (4H), 3.32 (m, 1H), 3.62 (m, 1H), 4.13 (d, 1H), 4.79 d, 1H), 6.88 (d, 1H), 7.05-7.30 (4H), 7.46 (d, 1H), 7.52 (d, 1H), 8.00 (d, 1H).
Reaction SMILES: [CH2:1]([S:3][CH:4]=[CH:5][N:6]1[CH2:10][CH2:9][NH:8][C:7]1=[N:11][N+:12]([O-:14])=[O:13])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:8]2[CH2:9][CH2:10][N:6]([CH:5]=[CH:4][S:3][CH2:1][CH3:2])[C:7]2=[N:11][N+:12]([O-:14])=[O:13])=[CH:18][N:17]=1
Reactant: CCSC=CN1CCNC1=N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCSC=CN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture comprising 8.0 g of 1-(2-ethylthiovinyl)-2-nitroiminoimidazolidine, 7.2 g of 2-chloro-5-chloromethylpyridine, 20.0 g of potassium carbonate .and 30 ml of dimethylsulfoxide was stirred at 60° C. for 30 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO) and concentrated to give an oily residue. This was purified by column chromatography silica gel, eluent: ethyl acetate/hexane 4/1) to give 8.3 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2-ethylthiovinyl)imidazolidine.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:15])[NH:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[NH:11][C:10](=[O:14])[NH:9][C:8]2=[O:15])([O-:18])=[O:17]
Reactant: O=c1[nH]c(=O)c2ccc([N+](=O)[O-])cc2[nH]1
Reactant: O=[N+]([O-])O
Product: O=c1[nH]c(=O)c2cc([N+](=O)[O-])c([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
10 g (48.3 mmol) of 7-nitro-1,2,3,4-tetrahydro-quinazoline-2,4-dione were added portionwise at 0° C. to 32 ml of fuming nitric acid. Thereafter, the mixture was stirred at room temperature for a further 5 hrs. The reaction mixture was poured on to ice, the precipitate was filtered off under suction and washed with 65% nitric acid, dilute nitric acid and finally with water. 7.15 g (59%) of 6,7-dinitro-1,2,3,4-tetrahydroquinazoline-2,4-dione were obtained as a yellow powder;
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)=[O:5])C.[OH-].[K+].O>CO>[CH:11]([C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[NH:7][CH:8]=1)=[O:12]
Reactant: CCOC(=O)c1cc(C=O)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=Cc1c[nH]c(C(=O)O)c1

Procedure:
Refluxing 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester in 2 equivalents of potassium hydroxide in methanol:water followed by acidification to pH 3 at 0° C. gave 4-formyl-1H-pyrrole-2-carboxylic acid as a solid. MS m/z 140 [M+1].
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][CH2:5][O:6][CH2:7][CH3:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[CH2:7]([O:6][CH2:5][CH2:4][C:3]([CH:2]=[P:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOCCC(=O)CCl
Solvent: ClC(Cl)Cl
Product: CCOCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 53.3 %

Procedure:
A solution of 1-chloro-4-ethoxybutan-2-one (7.5 g.) and triphenylphosphine (13.5 g.) in chloroform (20 ml.) was saturated with nitrogen and heated at reflux under nitrogen overnight. The chloroform was removed in vacuo and the residue was dissolved in dichloromethane (35 ml.). Dry diethyl ether (300 ml.) was added to precipitate 4-ethoxy-2-oxobutyltriphenylphosphonium chloride (19 g.). This compound was added portionwise to a solution of sodium carbonate (10g.) in water (1000 ml.) and the mixture was stirred vigorously for 24 hours. The solution was extracted with diethyl ether, and the ethereal extracts were dried over magnesium sulphate. The solvent was removed by evaporation and the residue was cooled and triturated with petroleum ether (b.p. 60°-80° C.) to give 3-ethoxypropionylmethylenetriphenylphosphorane (10.0 g.), m.p. 63°-65° C. Elemental analysis: found C, 76.6; H, 6.5; P, 8.2%; C24H25O2P requires: C, 76.6; H, 6.7;P 8.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1)=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]5[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)=[O:23])[CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2sc(C(=O)C3CCNCC3)nc12
Reactant: O=C1COc2ccc(C(=O)CCl)cc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2sc(C(=O)C3CCN(CC(=O)c4ccc5c(c4)NC(=O)CO5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A mixture of (4-methoxy-benzothiazol-2-yl)-piperidin-4-yl-methanone (83 mg, 0.3 mmol) and 6-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one (68 mg, 0.3 mmol) in DMF (1 ml) was treated with DIPEA (50 μl, 0.3 mmol) and the mixture was stirred at RT overnight. The mixture was poured on water and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Crystallisation from ether gave 113 mg (81%) of title compound as a beige solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=2[C:19]([O:21]CC)=O)[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[NH3:26]>>[C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=2[C:19]([NH2:26])=[O:21])[CH:8]=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C)n1
Solvent: CO
Product: CC(C)(C)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
In a 100 mL round bottom flask, ethyl 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (539 mg, 1.61 mmol) was suspended in ammonia 7M in methanol (7.87 g, 10.0 mL, 70.0 mmol). Sealed and stirred at room temperature for 18 h. The solvents were evaporated and the residue dried in high vacuum to give clean 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (492 mg, 99.9% yield) as an off-white solid. 1H NMR (DMSO-d6) δ: 11.94 (s, 1H), 9.23 (s, 1H), 8.84 (s, 1H), 8.19 (s, 1H), 7.74 (t, J=7.9 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.92 (d, J=7.9 Hz, 1H), 1.34 (s, 9H); LC-MS 306.1, 308.1 [M+H]+.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(Cl)ncn1
Yield: 78 %

Procedure:
Next, 4.7 g of 4-hydroxy-6-tert-butylpyrimidine obtained in Step 1 and 14 mL of phosphoryl chloride were put in a 50 mL three-neck flask, and the mixture was heated and refluxed for 1.5 hours. After the reflux, phosphoryl chloride was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane, and washed with water and then a saturated aqueous solution of sodium hydrogen carbonate. Anhydrate magnesium sulfate was added to the obtained organic layer for drying. This mixture was subjected to gravity filtration, and the filtrate was condensed to give a solid. This solid was purified by silica gel column chromatography. As a developing solvent, a mixed solvent of hexane and ethyl acetate in a ratio of 10:1 (v/v) was used. The obtained fraction was condensed to give 4-chloro-6-tert-butylpyrimidine (white solid, yield of 78%). A synthetic scheme of Step 2 is shown in (a-2) below.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH:9]=[O:10].N>S(=O)(=O)(O)O>[Cl:6][C:7]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH:9]=[O:10]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1c(F)cccc1Cl
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1c(F)ccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Potassium nitrate (638 mg, 6.31 mmol) was dissolved in concentrated sulfuric acid (4.5 mL) and added dropwise to a stirred solution of 2-chloro-6-fluorobenzaldehyde (1.0 g, 6.31 mmol) at room temperature. The mixture was stirred 1 hour at room temperature and then poured into icewater (100 mL) under stirring. The resulting aqueous phase was basified to pH 10 by addition of 25% aqueous ammonia and subsequently extracted with dichloromethane (2×100 mL). The combined organic phases were dried over sodium sulphate, filtered and evaporated to give 2-chloro-6-fluoro-3-nitrobenzaldehyde (196MBT28-A, 1.16 g, 91%). Regioselectivity was confirmed by 13C-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:16][C:17]([NH2:24])([C:19]1[N:23]=[CH:22][O:21][N:20]=1)[CH3:18]>>[CH3:16][C:17]([NH:24][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])([C:19]1[N:23]=[CH:22][O:21][N:20]=1)[CH3:18]
Reactant: O=C(O)c1ccc(Cl)c(OCC2CC2)n1
Reactant: CC(C)(N)c1ncon1
Product: CC(C)(NC(=O)c1ccc(Cl)c(OCC2CC2)n1)c1ncon1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-methyl-1-[1,2,4]oxadiazol-3-yl ethylamine (CAN 1153757-41-5) as starting materials, MS (LC/MS): m/e=337.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:23](Br)[CH:24]=[CH2:25]>ClCCl.Cl>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([O:19][CH2:25][CH:24]=[CH2:23])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reactant: C=CCBr
Agent: Cl
Solvent: ClCCl
Product: C=CCOc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.017 g, 0.045 mmol) in dichloromethane (1 mL) was treated with N″-tert-butyl-N,N,N′,N′,N″,N″-hexamethylphosphorimidic triamide (0.016 g, 0.068 mmol), allyl bromide (0.011 g, 0.09 mmol) and stirred for 3 hours at 20 C. The product mixture was diluted with 10% aqueous HCl, extracted twice with dichloromethane (20 mL), and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.011 g of a clear oil. MS calculated for C18H21BrF3NO2+H: 420, observed: 420.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[N:7]([CH2:15][CH2:16][NH:17][C@H:18]1[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]1)[N:6]=[CH:5]2.O.[OH-].[Li+:28]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O-:13])=[O:12])[CH:10]=1)[N:7]([CH2:15][CH2:16][NH:17][C@H:18]1[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]1)[N:6]=[CH:5]2.[Li+:28]
Reactant: COC(=O)c1cc(Cl)cc2cnn(CCN[C@@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cc(Cl)cc2cnn(CCN[C@@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Yield: 120.5 %

Procedure:
A mixture of (S)-methyl 5-chloro-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate (525 mg, 1.5 mmol) from Step D above and lithium hydroxide monohydrate (183 mg, 4.4 mmol) in tetrahydrofuran/water (14 mL, 1:1) was stirred at room temperature until the reaction was complete by TLC (2-3 h). The solvent was removed under reduced pressure to give lithium (S)-5-chloro-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate as a green solid (641 mg, 100%): 1H NMR (300 MHz, CD3OD) δ 8.01 (s, 1H), 7.71 (s, 1H), 7.48 (s, 1H), 4.80 (t, J=6.6 Hz, 2H), 3.10-2.96 (m, 2H), 2.95-2.88 (m, 1H), 2.80-2.58 (m, 5H), 2.33-2.27 (m, 1H), 1.80-1.76 (m, 1H), 1.72-1.60 (m, 2H), 1.60-1.40 (m, 1H), 1.40-1.20 (m, 2H); MS (ESI+) m/z 349 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21]>>[OH:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]#[C:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#Cc2ccccc2)c1

Procedure:
Sonogashira reaction of 39 with ethynylbenzene gave tert-butyl 3-hydroxy-3-(3-(phenylethynyl)phenyl)propylcarbamate as brown oil. Yield (0.911 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.51-7.55 (m, 3H), 7.42-7.44 (m, 1H), 7.30-7.37 (m, 5H), 4.87 (bs, 1H), 4.74-4.76 (m, 1H), 3.46-3.51 (m, 1H), 3.41 (bs, 1H), 3.13-3.19 (m, 1H), 1.79-1.88 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]4[CH:17]([C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:1][C:2]1[C:10]2[N:9]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:8]3[CH2:11][CH2:12][N:13]4[CH:17]([C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1)[CH2:16][CH2:15][CH2:14]4
Reactant: c1cc(C2CO2)ccn1
Reactant: Cc1cc(C)c2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(c1)c1c(n2CC(O)c2ccncc2)CCN2CCCC12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
8,10-Dimethyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (700 mg, 2.92 mmol) in DMF (20 mL) was stirred at 0° C. for 5 min. NaH (580 mg, 14.60 mmol) was added slowly at 0° C. After 10 min. stirring, 4-(oxiran-2-yl)pyridine (710 mg, 5.87 mmol) was added and the reaction mixture was stirred at RT for 15 h. The reaction mixture was poured in ice-cold water (150 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was washed with water (6×300 mL), dried over anhydrous sodium sulfate and concentrated to obtain semi-solid residue that was washed with hexane (3×20 mL). The residue was suspended in ether (30 mL) stirred for 1 h. The suspension was filtered to give 200 mg of 2-(8,10-dimethyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.79 (d, 2H), 8.03 (d, 2H), 7.13 (s, 1H), 6.82 (s, 1H), 5.22 (dd, 1H),5.01 (t, 1H), 4.67 (dd, 1H), 4.48 (dd, 1H), 4.79 (m, 1H), 3.64 (t, 2H), 3.4 (m, 3H), 2.9 (m, 1H), 2.73 (s, 3H), 2.37 (s, 3H), 2.22 (m, 3H). Separation by chiral HPLC provided diastereomers II-125a-b.