Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([NH2:5])[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[CH2:15]([O:22][C:23](=[O:26])[CH2:24]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[ClH:1].[CH2:15]([O:22][C:23](=[O:26])[CH2:24][NH:5][CH2:2][CH:3]=[CH2:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCN
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCNCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of allylamine hydrochloride (5.0 g, 53.4 mmol) in tetrahydrofuran (100 mL) was added diisopropylethylamine (10 mL) and bromoacetic acid benzyl ester (3.06 g, 13.3 mmol) at 0° C. and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was added ethyl acetate and 1 N-hydrochloric acid solution, the organic layer was extracted, and the aqueous layer was extracted two times with ethyl acetate. The organic layers were collected, washed with sodium thiosulfate solution and brine, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and to the obtained oil was added 4N-Hydrogen chloride in 1,4-Dioxane (3.5 mL). The mixture was concentrated under reduced pressure and lyophilized to give the title compound (2.12 g, 8.79 mmol, 66%).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([N:24]3[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]3)=S)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1.FC(F)(F)C([O-])=O.[Hg+2].FC(F)(F)C([O-])=O>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:22]([N:24]4[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]4)=[N:21][CH:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)N4CCC(NC(=O)OC(C)(C)C)C4)cnc32)cc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Agent: [Hg+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(N4CCC(NC(=O)OC(C)(C)C)C4)n23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution of tert-butyl 1-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)-pyrrolidin-3-ylcarbamate (0.54 g, 1.0 mmol, Preparation #J.1) in THF (15 mL) was added DIEA (0.444 mL, 2.54 mmol) followed by mercury (II) trifluoroacetate (0.478 g, 1.12 mmol). The reaction mixture was stirred at ambient temperature for about 2 h and then saturated aqueous NaHCO3 (30 mL) and EtOAc (30 mL) were added. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concd in vacuo. The crude material was purified by chromatography on silica gel (40 g) eluting with 10-40% EtOAc in DCM to provide tert-butyl 1-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylcarbamate (0.411 g, 81%) as a yellow glass: LC/MS (Table 1, Method a) Rt=2.50 min; MS m/z: 497 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: O=[N+]([O-])c1ccccc1NCCCCO
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1NCCCCO
Reaction time: 3 h
Yield: 90.2 %

Procedure:
2-(4-Hydroxybutylamino)nitrobenzene (30 g) was dissolved in ethanol (200 ml) containing 10% palladium-on-carbon (1 g) and hydrogentated at room temperature for 3 hours under pressure (50 p.s.i.=344.7 kPa). The solution was filtered and evaporated under vacuum and the residue chromatographed on silica eluting with ethyl acetate. The fractions containing the product were evaporated under vacuum to give the title compound, (23.2 g), which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH:24]([C@H:26]([C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1)[CH3:27])[NH2:25].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:24]([C@H:26]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH3:27])[N:25]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)NN)cc1
Reactant: O=C(C#Cc1cc(Cl)cc(Cl)c1)c1cnc2ccccc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2cnc3ccccc3c2)cc1

Procedure:
To a solution of the intermediate from step C (152 mg, 0.46 mmol) in DMF (5 mL) was added the ethyl 4-[(1S)-1-hydrazinoethyl]benzoate hydrochloride (126 mg, 0.51 mmol) and triethyl amine (86 μL, 0.61 mmol). After stirring, the reaction mixture at room temperature for 2 hours it was concentrated in vacuo. The residue was diluted with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 10% ethyl acetate-hexanes. This material was then re-purified with 75% hexanes-dichloromethane to give the desired compound as the major product. 1H NMR (CDCl3, 500 MHz): 8.84 (d, J=2.0 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 8.03 (d, J=8.2 Hz, 2H), 7.99 (d, J=2.1 Hz, 1H), 7.83 (d, J=1.8 Hz, 2H), 7.78 (m, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.34 (t, J=1.8 Hz, 1H), 7.28 (d, J=8.2 Hz, 2H), 6.77 (s, 1H), 5.58 (q, J=7.1 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.02 (d, J=7.1 Hz, 3H), 1.4 (t, J=7.0 Hz, 3H). LC-MS: 4.64 min; (M+H)=516.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]#[N:8])[S:5][CH:6]=1.[CH3:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1)=[O:22]>>[CH3:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([C:7]#[N:8])[S:5][CH:6]=2)=[CH:25][CH:24]=1)=[O:22]
Reactant: N#Cc1cc(Br)cs1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2csc(C#N)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous General Procedure A using 4-bromo-thiophene-2-carbonitrile (CAS 18791-99-6) and [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone to give the title compound. (150 mg, 30% yield). MS (ES+) 380.2 (M+H)+
Reaction SMILES: P(O)(O)(O)=O.[CH3:6][C@@H:7]1[CH2:19][NH:18][CH2:17][C@@H:16]2[N:8]1[C:9]1[N:10]=[C:11]3[CH2:22][O:21][CH2:20][C:12]3=[CH:13][C:14]=1[CH2:15]2.[C:23](OC(=O)C)(=[O:25])[CH3:24].[OH-].[Na+]>O.ClCCl>[CH3:6][C@@H:7]1[CH2:19][N:18]([C:23](=[O:25])[CH3:24])[CH2:17][C@@H:16]2[N:8]1[C:9]1[N:10]=[C:11]3[CH2:22][O:21][CH2:20][C:12]3=[CH:13][C:14]=1[CH2:15]2
Reactant: C[C@@H]1CNC[C@H]2Cc3cc4c(nc3N21)COC4
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1C[C@H]2Cc3cc4c(nc3N2[C@H](C)C1)COC4
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.33 (5R,8aR)-5-Methyl-1,3,5,6,7,8,8a,9-octahydro-2-oxa-4,4b,7-triaza-cyclopenta[b]fluorene dihydrogenphosphate in 4 ml water was added a solution of 1.3 ml acetic acid anhydride in 4 ml dichloromethane and the pH of the mixture was adjusted to 12.00 by addition of 1N aqueous sodium hydroxide. The mixture was stirred at room temperature for 15 minutes. The phases were separated and the organic phase was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine dried over sodium sulfate and evaporated to dryness to yield 0.25 g of the title compound as slightly yellow oil (MS: 274.1 (M+H+)).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: BrCCc1ccccc1
Product: OCCN(CCO)CCc1ccccc1

Procedure:
2-[(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-amino]-ethanol was prepared according to the general method as outlined in example 1. Starting from diethanolamine (6.0 g, 57). and 2-bromo-ethylbenzene (9.0 g, 48.3 mmol). Yield 9 g, (90%); yellow oil; MS: 210 (M+H)+.
Reaction SMILES: S([CH:5]([CH2:17]C(OCCCCCCCC)=O)[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCC)=[O:7])(O)(=O)=O.[Na].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O>[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:7])[CH:5]=[CH2:17]
Reactant: CCCCCCCCOC(=O)CC(C(=O)OCCCCCCCC)S(=O)(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Product: C=CC(=O)OCCCC

Procedure:
98 parts of butyl acrylate and 2 parts of tricyclodecenyl acrylate were polymerized at 65° C. for 3 hours with stirring in 154 parts of water with addition of 2 parts of sodium dioctyl sulfosuccinate (70% strength) as emulsifier and 0.5 part of potassium persulfate. This gave an approximately 40% strength dispersion. The median particle size of the latex was about 100 nm.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:18]1([CH2:21][C:22]([NH2:30])([CH3:29])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:30][C:22]([C:23]3[N:27]=[C:26]([CH3:28])[O:25][N:24]=3)([CH3:29])[CH2:21][CH:18]3[CH2:19][CH2:20]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1cc(OCC(F)F)c(C2CC2)cn1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)F)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2,2-difluoroethoxy)pyridine-2-carboxylic acid (Example 145d) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 66e) as starting materials and isolated (66 mg, 72%); MS (ESI, m/z): 407.6 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])#[N:2].Cl.C(OCC)(=O)C>C(O)C.ClCCl.[Fe]>[NH2:17][C:16]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1cc(C(=O)c2ccccc2)ccc1N
Yield: 15.9 %

Procedure:
To a stirred refluxing mixture of 3-cyano-4-nitrobenzophenone (Method 6) (1.50 g) and iron powder (3.64 g) in ethanol (50 ml) was added dropwise over 0.5 hour a solution of concentrated hydrochloric acid (0.35 ml) in ethanol (14 ml) and reflux was maintained overnight. The hot mixture was filtered through diatomaceous earth and the reaction flask and diatomaceous earth pad was washed with three 50 ml portions of ethanol. The combined filtrate was evaporated to yield a tan solid. Chromatography (eluent 10% to 40% ethyl acetate gradient in dichloromethane) gave the title compound (0.21 g) as a tan solid. M.p. 158-160° C.;
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([NH2:37])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.O.CO.C(O)(=O)C.C(O)C.CCOCC>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([NH2:37])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(N)=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(N)=O
Yield: 74 %

Procedure:
A solution of 2.2 g of Boc-Tyr-DAla-Phe-Met-NH2 in 20 ml of 10% anisole in trifluoroacetic acid (TFA) was stirred for 30 min. Evaporation of the solvent gave a residue which was dissolved in 20 ml of water:methanol:acetic acid (94:5:1) and applied to a column of Amberlite XAD-2 (44-74 μm, 2.7×60 cm). The sample was eluted at 6 ml/min with a convex gradient formed from 2 L of water:methanol:acetic acid (94:5:1) into which was fed methanol:water:acetic acid (50:49:1). Evaporation of the product peak gave a syrup which was dissolved in 100 ml of ethanol and diluted with 100 ml of ether to give 1.37 g (66%) of H-Tyr-DAla-Phe-Met-NH2.HOAc, m.p. 210°-211° C., [α]D25 =45.21° (c, 1.00 in 10% acetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH2:12])[CH3:11])=[CH:5][C:4]=1[CH3:13].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH3:11])=[CH:5][C:4]=1[CH3:13]
Reactant: COc1ccc(CC(C)N)cc1C
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1ccc(CC(C)NS(=O)(=O)c2ccccc2)cc1C

Procedure:
(±)-1-(4-methoxy-3-methylphenyl)-2-aminopropane and benzenesulfonyl chloride are treated in the same manner as described in Example 61-(1) to give (±)-1-(4-methoxy-3-methylphenyl)-2-benzenesulfonylaminopropane.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:26]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=4)[CH:26]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)Oc1ccc(-c2cncc(CCl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(-c2cncc(COc3ccc(CCCCn4ccnn4)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
A solution of 56 mg (0.24 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 10 mg (0.24 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 74 mg (0.24 mmol) 3-Chloromethyl-5-(4-trifluoromethoxy-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 56 mg (49%) of the title compound as light brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:4][C:3]=1[CH3:9]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc(Br)c(C)c1
Reaction time: 2 h
Yield: 36.9 %

Procedure:
4-Bromo-3-methylaniline (5.00 g, 27 mmol) and triethylamine (4.5 ml, 32 mmol) were stirred in dichloromethane (200 ml) as ethyl chloroformate (3.1 ml, 32 mmol) was added dropwise. The mixture was stirred for 2 h, when water was added. After stirring for a further 15 min, the white precipitate was filtered off, and the filtrate was separated. The organic portion was dried (Na2SO4) and evaporated to give the title compound (2.57 g, 37%) as an orange-brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[C:17]([F:18])([F:19])[F:20])[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)cn1
Yield: 81.7 %

Procedure:
A mixture of 4-methylimidazole (0.63 g, 7.67 mmol), 1-fluoro-2-(trifluoromethyl)-4-nitrobenzene (1.06 g, 5.1 mmol), and K2CO3 (1.06 g, 7.67 mmol) in acetonitrile (20 mL) was refluxed for 6 hs. The mixture was filtered through Celite and filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel (PE/EtOAc 1:1) to give 1.13 g product as light green oil (81.8%). 1H NMR (300 MHz, CDCl3) δ: 8.71 (1H, s), 8.52-8.55 (1H, d, J=8.4 Hz), 7.59-7.62 (2H, m), 6.90 (1H, s), 2.32 (3H, s). LCMS: m/z [M+H]+ 272.0660.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH:13][CH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[N:3]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][OH:13])[CH:20]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: O=Cc1c(Cl)n(-c2cccc(CO)c2)c2ccccc12
Yield: 17 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 3-(hydroxymethyl)-phenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(3-hydroxymethylphenyl)-1H-indole-3-carboxaldehyde (17% yield) as a pink solid. ESI/MS 286 (M+H); RT=2.85 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15]>>[CH2:11]([O:12][CH2:13][CH2:14][CH2:15][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:10][CH3:9]
Reactant: CCCOCCCCl
Reactant: O=C1CCNCC1
Product: CCCOCCCN1CCC(=O)CC1

Procedure:
1-(3-Propoxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-propoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(O)C.Cl[CH:13]([CH:19]=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:8]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1cc(F)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(F)ccn12
Temperature: 60 °C

Procedure:
4-Fluoropyridin-2-amine (10.0 g, 48.0 mmol) was mixed with ethanol (40 mL) in a reaction flask under an atmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene, 178 mL; commercial solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60° C. under nitrogen for 4 hours. After allowing the mixture to cool the solvent was removed under vacuum to give a brown solid. The solid was mixed with ethyl acetate (300 mL) and sodium bicarbonate solution (75 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted further with ethyl acetate (75 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give a solid. The crude material was dissolved in ethyl acetate and passed through a short column of silica, eluting with ethyl acetate to give ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate as a white solid (13 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:37])[N:15]=[C:16]([NH:17][CH2:18][C@@H:19]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:11]=2[CH:10]=[CH:9]1)C.[NH:39]1[CH2:44][CH2:43][CH2:42][N:41]=[C:40]1[NH2:45]>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[C@@H:19]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:18][NH:17][C:16]1[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH:45][C:40]3[NH:41][CH2:42][CH2:43][CH2:44][N:39]=3)[C:12]=2[N:13]=[C:14]([CH3:37])[N:15]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)CCCn1ccc2c(NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)nc(C)nc21
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: Cc1nc(NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 104 mg (0.19 mmol) of 4-{4-[(2S)-2-tert-butoxycarbonyl-2-(benzenesulfonylamino)-ethylamino]-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl}-butyric acid ethyl ester (example 4a) in 1 ml of DMF was aded 100 mg (1.0 mmol) of 1,4,5,6-tetrahydro-pyrimidin-2-ylamine and the reaction mixture was stirred at room temperature for 4.5 hours. The solvent was removed in vacuo the residue was taken up in DCM and washed with a saturated NaCl solution. The organic phase was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/MeOH/AcOH/H2O (95:5:0.5:0.5). Yield: 70 mg.
Reaction SMILES: Cl.CN1C(SC[CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][NH:11]2)=NN=N1.C(=O)(O)[O-].[Na+].O1CCCC1.Cl[C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34]>O>[Cl:38][C:37]([Cl:40])([Cl:39])[CH2:36][O:35][C:33]([CH:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=2)[CH2:13][CH2:12][NH:11]1)=[O:34]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1nnnc1SCC1NCCc2cc(O)c(O)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCC(Cl)(Cl)Cl)C1NCCc2cc(O)c(O)cc21
Yield: 78.2 %

Procedure:
A suspension of 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (50 g) in water (300 ml) was dissolved at 61° to 65° C. To the solution was added sodium bicarbonate (13.3 g) over 15 minutes at the same temperature. Tetrahydrofuran (250 ml) was added to the suspension at 50° C. The suspension was cooled and weakly alkalified by adding sodium bicarbonate (30 g) at 0° to 3° C. To the mixture was added 2,2,2-trichloroethyl chloroformate (40.2 g) over 30 minutes below 3° C. Water (300 ml) was added to the reaction mixture and the mixture was twice extracted with ethyl acetate (900 ml and 600 ml). The extract was washed with a sodium chloride aqueous solution (300 ml) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized with ether to give 1-(1-methyl- 1H-tetrazol-5-yl)thiomethyl-2-(2,2,2-trichloroethoxycarbonyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (40.4 g), mp 201° to 207° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:12]([CH3:14])[CH3:13])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>>[CH:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)([CH3:14])[CH3:13]
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: CC(C)c1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C(C)C)ccc23)c1

Procedure:
The product from Example 8b (100 mg, 0.435 mmol) was reacted with the product from Example 4c (105 mg, 0.435 mmol) for 18 h following the procedure from Example 1g producing the crude title compound that was purified by HPLC with TFA giving the trifluoroacetic acid salt (90 mg, 47%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (d, J=6.62 Hz, 6H), 2.13-2.30 (m, 1H), 2.33 (s, 3H), 2.89 (d, J=6.99 Hz, 2H), 6.29 (d, J=6.99 Hz, 1H), 6.73 (d, J=8.46 Hz, 2H), 7.00 (d, J=8.09 Hz, 1H), 7.13-7.34 (m, 4H), 7.81 (d, J=8.46 Hz, 1H), 8.43 (d, J=6.99 Hz, 1H), 9.03 (d, J=8.46 Hz, 1H), 10.99 (br. s., 1H), 14.36 (br. s., 1H); MS ESI+ m/z 416 (M+H)+; ESI− m/z 414 (M−H)−.