Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][N:14]3[C:19](=[O:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:30][CH2:31][C:32](Cl)=[O:33]>CCN(C(C)C)C(C)C>[O:21]([CH2:20][C:19]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]1[C:10]1[NH:11][N:12]=[C:8]([C:4]2[CH:3]=[C:2]([N:1]3[CH2:30][CH2:31][C:32]3=[O:33])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(-c2n[nH]c(C3CCCCN3C(=O)COc3ccccc3)n2)c1
Reactant: O=C(Cl)CCBr
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN1c1cccc(-c2n[nH]c([C@H]3CCCCN3C(=O)COc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
75 mg of 1-{2-[5-(3-Amino-phenyl)-2H-[1,2,4]triazol-3-yl]-piperidin-1-yl}-2-phenoxy-ethanone were dissolved in MDF and 40 ul DIPEA added. 34 mg of 3-Bromo-propionyl chloride were added at 0° C. and the reaction warmed up to rt and stirred for another 30 min. The reaction mixture was heated to 120° C. using microwave heating and the product was isolated via preparative HPLC.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCN(CC)CC.[Na+].[Cl-]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][C@@H:4]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(S)-tert-Butyl 4-hydroxy-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate was dissolved in 60 mL DCM and cooled to 0° C. MsCl (773 mL, 10 mmol) and Et3N (1.67 mL, 12 mmol) were added and the reaction was stirred for 1.5 hours at 0° C. NaCl (saturated, aqueous) was added, and the mixture was extracted with DCM (3×100 mL), dried over MgSO4 and evaporated. The title compound was obtained as an off-white solid and used without further purification in the next step. LCMS (API-ES) m/z (%): 411.1 (100%, M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH2:32]([S:39](Cl)(=[O:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)Cc4ccccc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and benzylsulfonyl chloride. Purity (ELSD, based on MW=575.7)=80%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][C@@H:9]2[C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[SH:22]>>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[S:22][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C@H:9]([OH:13])[C:10]([NH2:12])=[O:11]
Reactant: Cc1ccc([C@H]2O[C@@H]2C(N)=O)cc1
Reactant: Cc1ccc(N)c(S)c1
Product: Cc1ccc([C@@H](Sc2cc(C)ccc2N)[C@H](O)C(N)=O)cc1

Procedure:
(2S,3R)-3-(4-Methylphenyl)-2,3-epoxypropionamide and 2-amino-5-methylthiophenol are treated in the same manner as in Reference Example 1-(2) to give (2R,3R)-3-(2-amino-5-methylphenylthio)-2-hydroxy-3-(4-methylphenyl)propionamide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[CH2:46]=O>>[OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[CH2:41]2)=[O:37])=[O:30])[CH2:3]1
Reactant: C=O
Reactant: O=C(NC[C@@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CN1CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenypropanoyl)pyrrolidin-2-yl}carbonyl-N-((3R)-3-piperidyl-methyl)pyrrolidine-2-carboxamide and 37% aqueous formaldehyde solution. The compound was obtained as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[F:14][C:15]([F:19])([F:18])[CH2:16][NH2:17].CS(C)=O>O>[N+:11]([C:6]1[CH:7]=[C:8]2[CH2:9][N:17]([CH2:16][C:15]([F:19])([F:18])[F:14])[CH2:2][CH2:3][N:4]2[N:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Reactant: NCC(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc2n(n1)CCN(CC(F)(F)F)C2
Temperature: 120 °C
Yield: 78.3 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 124c (632 mg, 2.0 mmol), 2,2,2-trifluoroethanamine (594 mg, 6.0 mmol), and DMSO (5 mL), and heated at 120° C. for 2 h. The mixture was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combiner organic layer was dried and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silical-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 134a (392 mg, 78%) as a yellow solid. MS-ESI: [M+H]+ 250.9
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[Cl:30][C:31]1[CH:32]=[N+:33]([O-:56])[CH:34]=[C:35]([Cl:55])[C:36]=1[CH2:37][C@@H:38]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH:47]([F:49])[F:48])=[C:42]([O:50][CH2:51][CH:52]2[CH2:54][CH2:53]2)[CH:41]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:30][C:31]1[CH:32]=[N+:33]([O-:56])[CH:34]=[C:35]([Cl:55])[C:36]=1[CH2:37][C@@H:38]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH:47]([F:49])[F:48])=[C:42]([O:50][CH2:51][CH:52]2[CH2:54][CH2:53]2)[CH:41]=1)[O:24][C:23](=[O:25])[CH2:22][CH2:21][O:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a mixture of 3-(trityloxy)propanoic acid (0.5 g, 1.504 mmol) and EDC (0.865 g, 4.51 mmol) in dry DCM (20 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.632 g, 1.504 mmol) and DMAP (0.184 g, 1.504 mmol) were added, and the resulting solution was stirred at RT overnight. The solvent was evaporated and the residue was partitioned between EtOAc and a sat. sol. of NaHCO3. The organic layer was washed with aqueous 3% citric acid, with brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel column (DCM:MeOH: 32% aq. NH4OH=98:2:0.2) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(trityloxy)propanoyloxy)ethyl)pyridine 1-oxide (0.6 g, 0.817 mmol, 54.3% yield, MS/ESI+ 756.3 [MNa]+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([CH3:7])[CH2:5][OH:6].Cl[C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][N:11]=1>C1COCC1>[F:3][C:4]([F:8])([CH3:7])[CH2:5][O:6][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][N:11]=1
Reactant: CC(F)(F)CO
Reactant: N#Cc1cncnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(F)(F)COc1ncncc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a suspension of sodium hydride (60% dispersed in mineral oil, 1.84 g, 46 mmol) in THF (30.0 mL) was added 2,2-difluoropropan-1-ol (4.42 g, 46.0 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 h, then 4-chloropyrimidine-5-carbonitrile (6 g, 43.2 mmol) was added in portions at 0° C. After addition, the reaction mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (4.40 g, 22.1 mmol, 51% yield) as a yellow solid. MS (ESI) m/z 200.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[Br:15]Br.C(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[Br:15][CH2:13][C:12]([C:4]1[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)=[O:14]
Reactant: COc1cc(C(C)=O)cc(Cl)c1OC
Reactant: BrBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)CBr)cc(Cl)c1OC
Temperature: 25 °C

Procedure:
1-(3-Chloro-4,5-dimethoxyphenyl)-ethanone (31.6 g) was dissolved in chloroform (140 ml) and the solution was stirred at room temperature and treated dropwise with a solution of bromine (7.9 ml) in chloroform (60 ml). After a further 45 min the mixture was neutralised with aqueous potassium bicarbonate solution. The organic layer was separated and washed with sodium chloride solution, dried over sodium sulphate, then filtered and evaporated to dryness. The resultant oil (42.8 g) was crystallized from ether-hexane to give 2-bromo-1-(3-chloro-4,5-dimethoxyphenyl)-ethanone (32.0 g), m.p. 76.5°-78° C.
Reaction SMILES: [CH3:1][Al](C)C.[O:5]1[C@@H:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:6]1[CH2:7][OH:8]>Cl>[OH:5][C@H:6]([C@H:9]([CH3:1])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][OH:8]
Reactant: OC[C@@H]1O[C@H]1CCc1ccccc1
Reactant: C[Al](C)C
Agent: Cl
Product: C[C@H](CCc1ccccc1)[C@@H](O)CO
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a 5 L 3-neck round-bottom flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet was added a mixture of hexanes (IL). The vessel was cooled to 0° C. A 2.0M solution of Me3Al in hexanes (800 mL, 1.6 mol) was added, followed by a solution of epoxide 16 (120 g, 0.677 mol) in hexanes (250 mL)/CH12C12 (50 mL), maintaining the temperature below 20° C. Upon complete addition, the cloudy reaction mixture was stirred at 5° C. for 35 min. Then a solution of 10% HCl (300 mL) was added dropwise, followed by the addition of conc HCl (350 mL). The layers were separated, and the organic phase was washed with brine and dried over MgSO4. After removal of the volatiles in vacuo, the title compound (122.1 g) was obtained as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1
Reactant: COCCN
Reactant: Cc1nc(F)ccc1[N+](=O)[O-]
Product: COCCNc1ccc([N+](=O)[O-])c(C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 107.9 %

Procedure:
A mixture of 2-fluoro-5-nitro-6-picoline (656 mg, 4.2 mmol) and 2-methoxyethylamine (365 μl, 4.2 mmol) was stirred at 0° C. After 10 min, crude (2-methoxy-ethyl)-(6-methyl-5-nitro-pyridin-2-yl)-amine (957 mg) was obtained as a solid. 1HNMR (CDCl3, 400 MHz) δ 2.77 (s, 3H), 2.85 (s, 2H), 3.40 (s, 3H), 3.57-3.60 (m, 2H), 5.51 (s br, 1H), 6.26-6.29 (m, 1H), 8.18-8.20 (m, 1H). Exact mass calculated for C9H13N3O3 211.10. found 212.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCCCCCC(=O)OC)ccc(C(C)=O)c1O
Yield: 73.2 %

Procedure:
A mixture of 1.00 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 1.44 g of methyl 11-bromoundecanoate and 1.00 g of anhydrous potassium carbonate in 20 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 2 hours. The usual workup followed by chromatography on 30 g of silica gel and elution with 10% ethyl acetate-toluene gave 1.48 g (76% yield) of 11-(4-Acetyl-3-hydroxy-2-propylphenoxy)undecanoic acid methyl ester, the titled compound, as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[N:3]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncnc(NCCc3ccc(S(N)(=O)=O)cc3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:17][C:16]3([CH3:19])[CH2:18][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]3)=[O:10])=[CH:5][CH:4]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:17][C:16]3([CH3:19])[CH2:18][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]3)=[O:10])=[CH:5][CH:4]=1)[S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Solvent: ClCCl
Product: CN(c1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1)S(C)(=O)=O
Reaction time: 4 h
Yield: 50.6 %

Procedure:
To a mixture of (4-methylamino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (0.7 g, 2.44 mmol), DCM (40 ml) and TEA (0.7 ml, 4.89 mmol) was added methansulfonyl chloride (285 μl, 3.67 mmol). The resulting mixture was stirred for 4 hrs. at room temperature followed by evaporation of the volatiles in vacuo. The residue was dissolved in diethyl ether (10 ml), washed with water (2×10 ml) evaporated and the residue purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness. The residue was crystallized from diethyl ether (10 ml), filtered off and dried in vacuo at 50° C. affording 0.45 g (51%) of the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Br[C:35]([CH3:41])([CH3:40])[C:36]([NH:38][CH3:39])=[O:37]>>[CH3:39][NH:38][C:36](=[O:37])[C:35]([CH3:41])([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:6]=[C:5]([N:24]2[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]2[CH3:33])[N:4]=3)[CH2:13][CH2:14]1)[CH3:40]
Reactant: CNC(=O)C(C)(C)Br
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Product: CNC(=O)C(C)(C)N1CCC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and 2-bromo-N,2-dimethylpropanamide were reacted to give 585. LCMS m/z: 273.8 (2M+H+)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1)=[CH:11][CH:10]=3.Cl.[F:36][C:37]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O.CCOC(C)=O>[F:36][C:37]1([F:42])[CH2:41][CH2:40][N:39]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:11][CH:10]=4)[CH2:38]1
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(N3CCC(F)(F)C3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 22.4 %

Procedure:
A vial was charged with (S)-tert-butyl (3-chloro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-yl)carbamate (290 mg, 0.58 mmol), RuPhos-precatalyst (42.4 mg, 0.058 mmol) and 3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol). The vial was sealed before evacuating and backfilling with nitrogen. The solids were suspended in 1,4-dioxane (2 mL) before adding lithium bis(trimethylsilyl)amide solution (1.0M in THF; 2.33 mL, 2.33 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 20 h. Additional amounts of 3,3-difluoropyrolidine HCl (167 mg, 1.16 mmol), lithium bis(trimethylsilyl)amide solution (1.0M in THF; 1.16 mL, 1.162 mmol), and RuPhos-precatalyst (42.4 mg, 0.058 mmol) were added. After 23 h total reaction time, additional amounts of 3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol), lithium bis(trimethylsilyl)amide solution (1.0M in THF; 1.16 mL, 1.16 mmol), and RuPhos-precatalyst (42.4 mg, 0.058 mmol) were added. After 29 h total reaction time, additional amounts of 3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol), lithium bis(trimethylsilyl)amide solution (1.0M in THF; 1.16 mL, 1.16 mmol), and RuPhos-precatalyst (42.4 mg, 0.058 mmol) were added. After 45 h total reaction time, the reaction was diluted with water and EtOAc. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude was purified by silica gel chromatography to afford (S)-tert-butyl (3-(3,3-difluoropyrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-yl)carbamate (76.1 mg, 0.13 mmol, 23.0% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=2)=[O:25])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccc([N+](=O)[O-])cc1

Procedure:
The procedure described in Example 8 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.65 g of 4'-nitroacetophenone. Yield 1.25 g (38%), m.p. 255°-256° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])[CH:9]=[O:10])=[CH:4][CH:3]=1.[CH3:12][Li]>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])[CH:9]([OH:10])[CH3:12])=[CH:4][CH:3]=1
Reactant: C=C(C=O)c1ccc(C)cc1
Reactant: [Li]C
Solvent: CCOCC
Product: C=C(c1ccc(C)cc1)C(C)O
Temperature: -78 °C

Procedure:
2.34 g of aldehyde 38 is dissolved in 150 ml of diethyl ether and cooled to −78° C. under nitrogen. 20 ml of methyllithium solution (1.6 M in diethyl ether) is now added in drops. After 1.5 hours at this temperature, it is quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel with ethyl acetate/hexane, whereby in addition to 237 mg of starting material, 1.06 g of title compound 39 accumulates as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:19][NH2:20]>>[NH:19]([C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:20]
Reactant: NN
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Solvent: O
Product: NNc1cc(-c2ccccc2)c2ccccc2n1

Procedure:
Refluxing a 2-chloro-4-phenylquinoline (I) with hydrazine hydrate to give a 2-hydrazino-4-phenylquinoline (II);
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([CH2:12][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: O=Cc1ccc([N+](=O)[O-])c(Br)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Br)c2)CC1
Reaction time: 2 h
Yield: 87.8 %

Procedure:
N-methyl piperazine (0.95 mL, 8.56 mmol) was added dropwise to a suspension of 3-bromo-4-nitrobenzaldehyde (0.985 g, 4.28 mmol) and acetic acid (0.29 mL, 5.14 mmol) in toluene (5.5 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature before the addition of sodium triacetoxyborohydride (1.36 g, 6.42 mmol). The reaction mixture was stirred for 2 h. Further toluene (2.1 mL) and sodium triacetoxyborohydride (0.18 g, 0.86 mmol) was added and the reaction mixture was stirred for 2 hours and then quenched by the addition of MeOH (0.99 mL). The reaction mixture was stirred for 30 min, saturated aqueous NaHCO3 (6.01 mL) was then added and the reaction mixture was stirred overnight. The phases were separated and the aqueous layer was extracted with toluene (4.0 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash column chromatography (EtOAc:MeOH:NEt3 9:1:0.1) to give the title compound (1.18 g, 88%) as a low melting point waxy brown solid.