Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].C([O-])([O-])=O.[K+].[K+].[F:18][C:19]([P:25](Cl)[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])([F:24])[C:20]([F:23])([F:22])[F:21]>C(Cl)Cl>[F:24][C:19]([P:25]([C:26]([F:31])([F:32])[C:27]([F:28])([F:29])[F:30])[O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])([F:18])[C:20]([F:23])([F:22])[F:21]
Reactant: FC(F)(F)C(F)(F)P(Cl)C(F)(F)C(F)(F)F
Reactant: C=CCCCCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCCCCCCCCOP(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.31 g (1.9 mmol) of 9-decen-1-ol is initially introduced in CH2Cl2 with excess K2CO3, and 0.64 g (2.1 mmol) of bis(pentafluoroethyl)phosphinous acid chloride, (C2F5)2PCl, is condensed in. After the mixture has been stirred at room temperature for 30 minutes, the precipitate is filtered off, and volatile substances are removed in vacuo. The product, 9-decenyl bis(pentafluoroethyl)phosphinite, remains as a colourless, oily liquid, which is characterised by spectroscopy.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=O)(C)(C)C.[C:15](OC(=O)C)(=O)C.[ClH:22].O1CCOCC1>C(Cl)Cl>[ClH:22].[C@H:9]12[CH2:14][C@H:12]([NH:11][CH2:10]1)[CH2:13][N:8]2[C:6](=[O:5])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.00 g, 5.04 mmol) in DCM (15 mL) is added acetic anhydride (0.52 mL, 5.55 mmol) and the reaction stirred at about 25° C. for 72 hours. The reaction is concentrated, and the residue dissolved in DCM (15 mL) and treated with 4M HCl in 1,4-dioxane (5.04 mL, 20.2 mmol). The reaction is stirred overnight, and the solid filtered to afford the title compound (O).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[OH-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:8]=1)(=[O:18])[CH3:17]
Reactant: Nc1cccc(-c2ccccn2)c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2f (5.6g, 32.9mmol) and acetic anhydride (20ml) is stirred at ambient temperature for 1 hour. The mixture is poured into ice-water and rendered alkaline with 10M sodium hydroxide. The product is filtered off, washed with water and dried. Yield:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[NH:22][C:23]([NH2:25])=[O:24]>C(O)C.[Ni]>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH:15]=[N:16][NH:22][C:23]([NH2:25])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNC(N)=O
Reactant: N#CCCCOc1cccc(CN2CCCCC2)c1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: NC(=O)NN=CCCCOc1cccc(CN2CCCCC2)c1
Yield: 76.4 %

Procedure:
A solution of 4-[3-(1-piperidinylmethyl)phenoxy]butannitrile (51.6 g) sodium acetate (73.8 g) and semicarbazide hydrochloride (77.6 g) in 50% aqueous ethanol (1 L) was hydrogenated over Raney Nickel (50 g). The catalyst was removed by filtration. The filtrate was partially evaporated, made basic with potassium carbonate and extracted with ethyl acetate. The organic extract was evaporated to leave an oil which was purified by column chromatography to give the title compound as a pale yellow oil (48.6 g); tlc System B, Rf 0.8.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCN(c2ccc(N)nc2)CC1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To 1-methyl-4-(6-nitro-3-pyridyl)piperazine 3.4 g in ethyl acetate (100 mL) and ethanol (100 mL) was added 10% Pd/c (400 mg) and then contents stirred under hydrogen (10 psi) overnight. After filtration through CELITE™, the solvents were evaporated and the crude product was purified over silica gel using DCM/7N Ammonia in MeOH (0-5%) to afford 5-(4-methylpiperazin-1-yl)pyridin-2-amine (2.2 g). 1HNMR (d6-DMSO) 7.56 (1H, d, J=3 Hz), 7.13 (1H, m), 6.36 (1H, d, J=8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:10]2[CH2:12][CH2:11]2)[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][NH2:23])=[N:19][CH:20]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:25])([F:13])[F:24])=[CH:20][N:19]=2)=[CH:3][C:4]=1[O:9][CH:10]1[CH2:12][CH2:11]1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: Clc1ccc(Br)cc1OC1CC1
Product: FC(F)(F)c1ccc(CCNc2ccc(Cl)c(OC3CC3)c2)nc1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-chloro-3-cyclopropoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 357.1 [M+H]+) was prepared from (4-bromo-1-chloro-2-cyclopropoxy-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl

Procedure:
To a solution of 2-chloro-3-nitro-5-trifluoromethylbenzoic acid (1.35 g) in toluene (15 ml) are added 1.2 ml of SOCl2. After refluxing for 2 hours, the end of the reaction is confirmed by monitoring by infrared (new band at 1788 cm−1). The reaction medium is evaporated to dryness and the resulting yellow oil, 2-chloro-3-nitro-5-trifluoromethylbenzoyl chloride, is used without further purification in the following step.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: NC1CCCCC1
Product: COc1cc2ncc(NC3CCCCC3)nc2cc1OC
Temperature: 135 °C
Yield: 69 %

Procedure:
To 0.3 g (1.34 mmol) of 2-chloro-6,7-dimethoxyquinoxaline is added approx. 1 mL of cyclohexylamine. The mixture is heated overnight at 105° C. and a further 10 hours at 135° C. The mix is partitioned between CH2Cl2 and saturated NaHCO3. The organic layer is dried (MgSO4) and concentrated. The resulting syrup is chromatographed (1:1 EtOAc:CH2Cl2) to provide 0.265 g of the product as a It. brown solid in 69% yield (m.p. 188-189.5). Anal. calcd for C16H21N3O2: C, 66.88; H, 7.37; N, 14.62. Found: C, 66.82; H, 7.28; N, 14.45.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: CCCCCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Pan B) (0.040 g, 0.154 mmol), amylamine (0.0139 g, 0.154 mmol) and 3 Å molecular sieves in a vial. Add methanol (1.5 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load directly onto a 5 g SCX column. Wash with methanol (10 mL), then elute with 2.0 M NaBH3 in methanol. Purify by loading the product onto a 5 g loading cartridge and eluting through a 10 g ISCO® column with 50% ethyl acetate, 5% (2.0 M NH3 in methanol) and 45% hexanes to give the title compound (0.0387 g, 76.0%: TOF MS ES+ 332.2 (M+H)+. HRMS calcd for C18H23N3O2F 332.1774 (M+H)+, found 332.1765, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.9 min, 100% purity.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:21]=1[C:22](Cl)=[O:23]>O1CCCC1>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:21]=1[C:22]([N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: O=C(Cl)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: c1ccc(-c2ncc[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1c(Cl)cccc1[N+](=O)[O-])n1ccnc1-c1ccccc1

Procedure:
13.4 g of 2-phenylimidazole are dissolved in 120 ml of tetrahydrofuran; 9.7 g of triethylamine are added, and there are then added dropwise, at reflux temperature within 10 minutes, 20.5 g of 2-chloro-6-nitro-benzoyl chloride, dissolved in 40 ml of tetrahydrofuran. The mixture is refluxed for 1 hour, and the precipitated triethylamine hydrochloride is removed at room temperature by filtration in vacuo. After removal of the solvent in the rotary evaporator, the crude product is recrystallised from 65 ml of acetonitrile. The yield is 25.1 g (82.4% of theory) of product, m.p. 147°-148° C. Concentration of the mother liquor by evaporation produces a further 2.1 g (6.9% of theory) of this product, m.p. 144°-147° C.
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=4[Cl:27])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:27].[C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:43])[NH2:26])=[CH:21][C:20]=4[Cl:27])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1Cl)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1Cl)n2C)c1ccccc1
Yield: 82 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-chloro-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 82% of theory, C28H29ClN6O3 (533.1) ##EQU101##
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:12](=O)([O:18]N1C(=O)CCC1=O)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].CO>O.[OH-].[K+]>[C:14]([O:13][C:12]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To the solution of 575 mg of lysine monohydrochloride in 2 ml of water, 6.2 ml of 1N methanolic potassium hydroxide was added and then 645 mg of t-butyl succinimidyl carbonate in 3 portions was mixed in over 20 minutes while stirring at room temperature. Stirring was continued for another 2 hours, then the reaction mixture was acidified to pH 5, methanol evaporated and the white precipitate collected by filtration giving 779 mg (quantitative yield) of the crude title compound. This was twice recrystallized from warm water to give 529.7 mg (68%) of pure compound.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([OH:22])([C:16]1[N:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:12]2)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:11]2([OH:22])[CH2:12][CH:13]3[NH:8][CH:9]([CH2:15][CH2:14]3)[CH2:10]2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cccnn1)C2
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2cccnn2)CC2CCC(C1)N2
Reaction time: 0.5 h

Procedure:
3-Hydroxy-3-pyridazin-3-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.22 g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 2.5 mL). The mixture was stirred for 0.5 hours and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound (0.22 g). LCMS m/z 206.2 [M+H]+. R.T.=0.35 min. (Analytical Method 3).
Reaction SMILES: Cl[C:2]([O:4][CH2:5]C)=[O:3].[NH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:11]1>N1C=CC=CC=1>[CH3:5][O:4][C:2]([NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:11]1)=[O:3]
Reactant: CCOC(=O)Cl
Reactant: NCCn1cc(Cc2ncc[nH]2)c2ccccc21
Solvent: c1ccncc1
Product: COC(=O)NCCn1cc(Cc2ncc[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
Ethyl chloroformate (0.19 g) was added dropwise to a stirred solution of 1-(2-aminoethyl)-3-(1-imidazolylmethyl)indole (0.48 g) in pyridine (5 ml) at room temperature. The solution was stirred at room temperature for 3 hours and then evaporated. The residue was stirred with aqueous sodium bicarbonate solution and the solid product was filtered off, washed with water, dried and crystallised from ethyl acetate/petrol (b.p. 60°-80° C.) to give 1-(2-methoxycarbonylaminoethyl)3-(1-imidazolylmethyl)indole (0.32 g), m.p. 78°-79° C. Found: C, 62.22; H, 5.99; N, 17.72. C16H18N4O2.1/2H2O requires: C, 62.52; H, 6.23; N, 18.23%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]#[N:19].Cl>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][N:8]2[CH2:17][C:18]#[N:19])=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2cc(Br)ccc12
Reactant: N#CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCn1cc(C(=O)O)c2ccc(Br)cc21
Temperature: 0 °C
Yield: 68 %

Procedure:
6-Bromo-1H-indole-3-carboxylic acid (0.24 g, 1 mmole) was dissolved in anhydrous dimethylformamide (2 ml) and cooled to 0° C. in a nitrogen atmosphere. With stirring, sodium hydride (60% in oil, 0.088 g, 2.2 mmole) was added all at once and the mixture was stirred at this temperature until no more bubbles evolved (ca. 20-30 minutes). Bromoacetonitrile (0.132 g, 1.1 mmole) was added to the reaction mixture which was then allowed to warm to room temperature over the next hour. The reaction mixture was poured into water, acidified with HCl and a precipitate formed. When dried the product weighed 0.190 g (68% yield) and was sufficiently pure to be used directly in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[Br:11]Br>C(O)(=O)C>[Br:11][C:6]1[C:7]([NH2:10])=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ncc([N+](=O)[O-])cc1Br
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
To a solution of 5-nitro-pyridin-2-ylamine (30 g, 0.22 mol) in acetic acid (200 mL) at 10° C. was added Br2 (38 g, 0.24 mol) dropwise. After addition, the mixture was stirred at 20° C. for 30 min. The solid was filtered and then dissolved in ethyl acetate (200 mL). The mixture was basified to pH 8-9 with saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to afford 3-bromo-5-nitropyridin-2-amine (14.8 g, 32%). 1H-NMR (CDCl3, 400 MHz) δ 8.94 (d, J=2.4 Hz, 1H), 8.50 (d, J=2.4 Hz, 1H), 5.67 (brs, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][OH:42])=[O:38])([CH3:35])([CH3:34])[CH3:33].O[C:44]1[CH:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:55][CH3:56])[O:46][N:45]=1>O1CCCC1>[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][O:42][C:44]1[CH:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:55][CH3:56])[O:46][N:45]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1ccccc1-c1cc(O)no1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(OCCNC(=O)OC(C)(C)C)no1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Triphenylphosphine (0.45 g) was dissolved in tetrahydrofuran (5 ml), and diethyl azodicarboxylate (0.27 ml) was added dropwise to the solution under ice-cooling with stirring, and the resulting mixture was stirred at the same temperature for 30 minutes. Then, 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) and 3-hydroxy-5-(2-methoxyphenyl)isoxazole (0.22 g) were added to the reaction mixture, followed by stirring of the resulting mixture under ice-cooling for 10 minutes and at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (0.33 g, 86%) as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)(O)[O-].[Na+].O>CO>[C:4]1([CH2:3][CH2:2][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(CCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2-Bromoethyl)benzene (41.62 g, 0.225 mol) was added dropwise to a stirred mixture of imidazole (13.6 g, 0.2 mol) and sodium bicarbonate (16.8 g, 0.2 mol) in methanol (100 ml). Following the addition, the reaction mixture was stirred at ambient temperature for 24 h, and then stirred and heated under reflux for 6 h. After concentration of the reaction mixture under reduced pressure, the residue was treated with water (100 ml), and this mixture was extracted with chloroform (3×75 ml). The combined extracts were dried (magnesium sulphate), and the solution was then evaporated under reduced pressure. The resulting brown oil was distilled to afford 1-(2-phenylethyl)imidazole, b.p. 122°/0.2 mmHg. The slightly impure product was purified using a silica gel column and by elution with ethyl acetate/methanol (9:1). The product fractions were pooled, concentrated, under reduced pressure, and then distilled, to afford the pure product, b.p. 110°/0.1 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:9]1[CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)(=[O:16])[CH3:15]
Reactant: Clc1cccc2c1CNCCS2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.6 g, prepared in a similar manner to its hydrochloride, Example 1 above) in acetic anhydride (15 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was dried and the solvent was removed by evaporation to give 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 1.68 g (m.p. 79°-81° C.).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:16]>CC(O)C>[CH:12]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:16])[C:3]3=[C:10]([I:11])[N:9]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Clc1nccn2c(C3CCC3)nc(I)c12
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(I)c12
Temperature: 115 °C

Procedure:
A Parr bomb containing 8-chloro-3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazine (759 mg, 2.3 mmol) in IPA (100 mL) was saturated with NH3(g) for 5 min at 0° C. then sealed and heated at 115° C. for 38 h. The reaction mixture was then concentrated under reduced pressure, partitioned between DCM (200 mL) and H2O (50 mL) and extracted with DCM (50 mL). Combined organic fractions were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a white solid; 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J=4.8 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 5.63 (br, 2H), 3.73 (quintetd, J=0.8 Hz, 8.4 Hz, 1H), 2.60-2.38 (m, 4H), 2.20-1.90 (m, 2H); MS (ES+): m/z 315.9 (100) [MH+]; HPLC: tR=1.75 min (OpenLynx, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=3[CH3:17])[N:7]([CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[C:6]=2[C:5]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=3[CH3:17])[N:7]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:6]=2[C:5]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2c(C)nn(C)c2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)nn(C)c3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
To a solution of ethyl 4-{4-chloro-7-(1-ethylpropyl)-2-[(1,3,5-trimethyl-1H-pyrazol-4-yl)amino]-1H-benzimidazol-1-yl}butanoate (240 mg, 0.52 mmol) in tetrahydrofuran (3 mL) was added lithium borohydride (34 mg, 1.57 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 0-10% methanol/ethyl acetate gradient mixture. The filtrate was concentrated in vacuo to give the title compound (74 mg, 0.17 mmol, 34%) as a colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:5]=[C:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: CC(=O)N(C)c1cc(Br)cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(=O)N(C)c1cc(Br)cc(S(=O)(=O)c2ccc(N)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
0.04 g (0.00009 mol) of N-[3-bromo-5-(4-nitrobenzenesulphonyl) -phenyl]-N-methylacetamide was dissolved in 5 ml of ethanol, treated while cooling with a solution of 0.085 g (0.00045 mol) of SnCl2.2H2O in 0.34 ml of HCl (37%) and stirred at room temperature for 18 hrs. Then, the solvent was removed and the residue was adjusted to pH 8 with sat. NaHCO3 solution. The aqueous phase was extracted with ethyl acetate and the organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and freed from solvent. There was obtained 0.021 g (61%) of N-[3-bromo-5-(4-aminobenzenesulphonyl)-phenyl]-N-methylacetamide as a light yellow oil. MS (ISN): me/e=443, 441 (C15H15BrN2O3S- +NaOAc).