Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[ClH:2].Cl.[NH2:4][CH2:5][C:6]([CH2:8][NH2:9])=O.Cl.[CH:11]1([CH2:14][O:15][NH2:16])[CH2:13][CH2:12]1.[CH3:17]O>>[ClH:2].[CH:11]1([CH2:14][O:15][N:16]=[C:6]2[CH2:8][NH:9][CH:17]=[N:4][CH2:5]2)[CH2:13][CH2:12]1
Reactant: NOCC1CC1
Reactant: NCC(=O)CN
Reactant: CO
Agent: Cl
Solvent: O
Product: C1=NCC(=NOCC2CC2)CN1
Yield: 57 %

Procedure:
1,3-Diaminoacetone dihydrochloride monohydrate (2.00 g, 11.2 mmol) was dissolved in refluxing methanol and O-(cyclopropylmethyl)hydroxylamine hydrochloride (2.60 g, 21.1 mmol) was added. After refluxing for 96 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux. After 48 hours the solvent was removed in vacuo. Crystallization from methanol/ethyl acetate afforded 1.30 g (57%) of light-brown material. Mp. 158.0° C.
Reaction SMILES: CS(OC[C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:9][CH2:8]1)(=O)=O.[CH3:30][NH:31][CH2:32][CH2:33][OH:34].[CH:35](N(CC)C(C)C)(C)C>C(#N)C.C([O-])(O)=O.[Na+]>[Br:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:25]([CH:27]1[CH2:29][CH2:28]1)=[O:26])=[C:14]2[NH:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:30][N:31]([CH2:32][CH2:33][OH:34])[CH3:35])[CH2:12][CH2:11]1
Reactant: CNCCO
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCO)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Temperature: 70 °C

Procedure:
To a solution of (trans-4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)cyclohexyl)methyl methanesulfonate (361 mg, 0.75 mmol) and 2-(methylamino)ethanol (0.30 mL, 3.75 mmol) in acetonitrile (15 mL) was added N,N-diisopropylethylamine (1.0 mL, 5.8 mmol) and the reaction mixture was heated at 70° C. for 16 h. The solution was cooled to room temperature, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded the desired product (150 mg, 43%) as an off-white solid. ESI MS m/z 460 [C23H30BrN3O2+H]+
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[O-2].[Ca+2:7]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:7].[Ca+2:7].[P:1]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [O-2]
Product: O=P([O-])([O-])[O-]
Product: [P]

Procedure:
Typically, the predetermined amounts of the aqueous solution of phosphoric acid, the calcium oxide containing product, e.g. the unslaked lime and the CMS are selected in a proportion to produce CMS-enriched calcium phosphate having a total phosphorus content of about 10-18% (mass/mass), a total calcium content of about 8,5-32,4% (mass/mass), and a Ca:P ratio (mass/mass) of between 1,8-1 and 0,85:1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:24][CH2:25][N:26](CC)CC.Cl.C(=N)(OCC)C>CO>[NH:26]=[C:25]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)[CH3:24]
Reactant: CCN(CC)CC
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: CCOC(C)=N
Agent: Cl
Solvent: CO
Product: CC(=N)N1CCC(N(Cc2ncccc2C)Cc2ncccc2C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.1 %

Procedure:
To a solution of COMPOUND 249 (0.1054 g, 0.34 mmol) in MeOH (4 mL) was added Et3N (0.1 mL, 0.68 mmol) and ethyl acetimidate hydrochloride (0.0549 g, 0.41 mmol), and stirred at room temperature for 24 hours then concentrated. Saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (2×40 mL). Purification of the crude material by column chromatography on silica gel (15:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (50:3:2 CH2Cl2-MeOH—NH4OH) provided 0.0408 g (34%) of COMPOUND 338 as a white solid. 1H NMR (CDCl3) δ 1.60-1.72 (m, 2H), 1.90-1.95 (m, 2H), 2.09 (s, 6H), 2.12 (s, 3H), 2.47-2.68 (m, 4H), 3.82 (s, 4H), 4.17 (d, 2H, J=12.3 Hz), 7.06-7.10 (m, 2H), 7.37 (d, 2H, J=7.2 Hz), 8.34 (d, 2H, J=4.5 Hz). 13C NMR (CDCl3) δ 18.39, 23.92, 27.33, 45.64, 55.06, 57.89, 122.77, 133.81, 138.40, 146.29, 157.63, 164.64. ES-MS m/z 352.5 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.[CH3:11][C:12]1[CH:18]=[C:17]([C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([CH3:25])=[CH:15][C:13]=1[NH2:14]>C(Cl)Cl>[CH3:6][N:7]([CH3:10])[CH:8]=[N:14][C:13]1[CH:15]=[C:16]([CH3:25])[C:17]([C:19]#[C:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:18][C:12]=1[CH3:11]
Reactant: Cc1cc(C#CC(C)(C)C)c(C)cc1N
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(N=CN(C)C)c(C)cc1C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
Phosphorus oxychloride (182 mg) was added to a mixture of 5 ml of dichloromethane and 145 mg of N,N-dimethylformamide at 25° C. After the mixture was stirred at 25° C. for 1 hour, 1 ml of a methylene chloride solution containing 200 mg of the 2,5-dimethyl-4-(3,3-dimethyl-1-butynyl)aniline (Compound 4-25) produced in Production Example 2 was added dropwise thereto. The mixture was stirred at 25° C. for 2.5 hours, and the reaction solution was then poured into ice water. The pH was adjusted to 11 with an aqueous 1 N potassium hydroxide solution, and extraction was performed 3 time with dichloromethane. The organic layer was collected, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), thereby obtaining 30 mg of N,N-dimethyl-N′-[2,5-dimethyl-4-(3,3-dimethyl-1-butynyl)phenyl]formamidine (Compound 52).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.C(OCC)(=O)C>[C:26]1([NH:25][C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
A solution of 2-chloro-6-trifluoromethyl-nicotinic acid (5 g, 22.2 mmol) in tetrahydrofuran (20 mL) cooled to −78° C. was treated with lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 66.5 mL, 66.5 mmol). This solution was stirred at −78° C. for 2 h. At this time, the reaction was treated with a solution of aniline (19.6 g, 19.2 mL, 210 mmol) in tetrahydrofuran (20 mL). The reaction was allowed to gradually warm to 25° C. and was stirred at 25° C. overnight. At this time, the reaction mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×150 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in ether to afford 2-phenylamino-6-trifluoromethyl-nicotinic acid (6.19 g, 96.9%) as a light brown solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>ClCCl>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)(=[O:40])=[O:39]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (100 mg, 0.314 mmol) and triethylamine (0.1 mL, 0.63 mmol) in anhydrous dichloromethane (3 mL) under nitrogen atmosphere at 0° C. was added 2-fluorobenzenesulfonylchloride (91 mg, 0.47 mmol). The reaction mixture was stirred for 2 h allowing it to warm up to room temperature. It was then diluted with dichloromethane and quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (120 mg, 80%). 1H NMR (400 MHz, CDCl3) δ7.86-7.82 (t, 1H), 7.58-7.52 (m, 1H), 7.28-7.24 (m, 1H), 7.13-7.12 (m, 3H), 6.90-6.88 (m, 2H), 4.19 (m, 1H), 4.05-4.02 (t, 2H), 3.73-3.70 (m, 2H), 3.56-3.51 (t, 2H), 3.10-3.08 (d, 2H), 2.66-2.62 (t, 2H), 2.54 (m, 4H), 2.06-1.99 (m, 4H), 1.85-1.8 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>>[O:21]=[C:19]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:10]1=2
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C

Procedure:
A sample of 4-benzyloxy-3-carboxyphenylacetic acid is treated with an excess of thionyl chloride at reflux for 2 hours. The excess thionyl chloride is removed in vacuo and the remaining 4-benzyloxy-3-(chlorocarbonyl)phenylacetyl chloride is dissolved in methylene chloride-nitromethane and treated with an equivalent amount of aluminum chloride. The reaction mixture is stirred several hours at room temperature, refluxed for two hours and quenched with dilute hydrochloric acid. The layers are separated, the organic phase dried and evaporated in vacuo to a residue which, on crystallization from isopropyl alcohol yields 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, mp 137°-138° C.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH2:9])[CH3:8])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1C=CC=CC=1>[C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH3:8])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OOC(C)(N)CC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OOC(C)(CC)NS(C)(=O)=O
Yield: 67.5 %

Procedure:
To a solution of 15.9 g of ethyl-β-amino-β-ethoxy acrylate in 60 ml of benzene was added 10.3 g of triethylamine, and a solution of 11.5 g of methanesulfonyl chloride in 40 ml of benzene was dropped thereinto with stirring. After the dropping, the resulting mixture was stirred at room temperature for 5 hours. The crystals formed were separated. The filtrate was concentrated under reduced pressure and the concentrated residue crystallized by cooling. When the crystals were washed with n-hexane and dried, 16 g of prismatic crystals of a melting point of 103° to 104° C. was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[C:28]([F:41])[CH:27]=2)[CH:19]=1.SCC(O)=O.O.[OH-].[Li+]>CN(C)C=O>[CH3:17][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[C:28]([F:41])[CH:27]=2)[CH:19]=1
Reactant: Cc1cc(OCCN2CCCC2=O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCN2CCCC2=O)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)OC(C)(C)C)c(F)c2)c1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of tert-butyl 3-(4-{({2′,6′-dimethyl-4′-[2-(2-oxopyrrolidin-1-yl)ethoxy]biphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate (0.91 g, 1.23 mmol) and mercaptoacetic acid (0.26 mL, 3.68 mmol) in N,N-dimethylformamide (9 mL) was added lithium hydroxide monohydrate (0.31 g, 7.38 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and to the residue was added brine. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate-=5/1-ethyl acetate) to give the title compound (0.51 g, yield 74%) as a colorless amorphous powder.
Reaction SMILES: CN(C)C=O.[CH2:6]([C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[S:16][C:17]=1Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].N>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:6]([C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[S:16][C:17]=1[C:29]#[C:28][C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Brc1sc(-c2ccc3c(c2)OCO3)nc1Cc1ccccc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2sc(-c3ccc4c(c3)OCO4)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
5 ml of N,N-dimethylformamide was added to a mixture of 377 mg of 4-benzyl-5-bromo-2-(3,4-methylenedioxyphenyl)thiazole, 178 mg of 3-ethynyl-3-quinuclidinol, 68 mg of tetrakis (triphenylphosphine)palladium(0), 18 mg of cuprous iodide and 0.5 ml of triethylamine, followed by heating under stirring at 100° C. in an oil bath for 15 minutes in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The resulting crystals were collected by filtration, to give 253 mg of the target compound.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH2:36][CH3:37])([CH3:35])[CH2:33][CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH2:33][CH3:34])([CH3:35])[CH2:36][CH3:37])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(C)(CC)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(CC)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 107b (1.8 g, 3.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (2.5 g, 91%).
Reaction SMILES: [CH3:1]OC(OC)N(C)C.[CH:9]([N:22]1[CH2:25][C:24]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:26]([NH2:28])=[O:27])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:9]([N:22]1[CH2:23][C:24]2([C:26](=[O:27])[N:28]=[CH:1][N:29]2[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC(=O)C1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COC(OC)N(C)C
Product: O=C1N=CN(Cc2ccccc2)C12CN(C(c1ccccc1)c1ccccc1)C2
Reaction time: 4 h
Yield: 61.7 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (16 ml, 121 mmol) was combined with 1-benzhydryl-3-benzylaminoazetidine-3-carboxylic acid amide (I-3A-50b; 3.03 g, 8.16 mmol) and heated to reflux. After 4 hours, the suspension was cooled and extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated, in vacuo, to give a crude solid (3.50 g). Purification of the residue on a Biotage™ Flash 40M column using 0-3% methanol in methylene chloride as eluant afforded I-3A-50c as a yellowish solid (1.92 g, 62%): +ESI MS (M+1) 382.3; 1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 7.59 (d, J=7.1 Hz, 2H), 7.49-7.11 (m, 13H), 5.12 (s, 2H), 4.44 (s, 1H), 3.31 (d, J=9.6 Hz, 2H), 3.20 (d, J=9.6 Hz, 2H).
Reaction SMILES: BrC1C(NC(=O)C(=O)CC(C)(C2C=CC=CC=2)C)=CC=C2C=1COC2=O.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:33](=[O:34])[O:32][CH2:31]2.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]([CH3:52])[CH2:46][C:47](=[O:51])[C:48](O)=[O:49])=[C:41]([O:53][CH3:54])[CH:40]=1>>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]([CH3:52])[CH2:46][C:47](=[O:51])[C:48]([NH:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[C:33](=[O:34])[O:32][CH2:31]3)=[O:49])=[C:41]([O:53][CH3:54])[CH:40]=1
Reactant: COc1cc(Br)ccc1C(C)CC(=O)C(=O)O
Reactant: Nc1ccc2c(c1)COC2=O
Agent: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Product: COc1cc(Br)ccc1C(C)CC(=O)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(4-bromo-2-methoxyphenyl)-2-oxo-valeric acid, melting point 136-140° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][C:12](=O)[CH2:13][CH2:14][CH3:15].[BH4-].[Na+]>>[CH3:11][CH:12]([NH:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(C)=O
Reactant: Nc1ccc2nc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCCC(C)Nc1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (399 mg; 3 mmol; 1 eq.), 2-pentanal (284 mg; 0.351 ml; 3.3 mmol; 1.1 eq) and NaBH4 (228 mg; 6 mmol; 2 eq.) as described in method 3; Yield: 0.264 g (43.3%); MS m/z: 204.4 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 0.88 (t, 3H, 3J=7.5 Hz); 1.10 (d, 3H, 3J=6.2 Hz); 1.32-1.42 (m, 3H); 1.49-1.56 (m, 1H); 3.35-3.37 (m, 1H); 5.02 (br s, 1H); 6.52-6.55 (m, 2H); 7.25 (d, 1H, 3J=8.7 Hz); 7.83 (s, 1H); 11.81 (br s, 1H); HPLC (METHOD [A]): rt 7.79 min (80.5%)
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])C)[C:27]([O:29]C)=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN(C4(C(OC)=O)CC4)C3=O)=CC=2)=CC=1.FC(F)(F)C1C=CC(C([Cl:66])=O)=CC=1>>[Cl:66][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([C:26]5([C:27]([OH:29])=[O:28])[CH2:33][CH2:31]5)[C:22]4=[O:25])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[O:8])=[CH:7][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CC1
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N(C2(C(=O)O)CC2)C3)cc1)c1ccc(Cl)cc1
Yield: 93 %

Procedure:
The compound of example 588 was prepared analogous to compound of example 97 by reaction of compound of example 584 with 4-trifluoromethyl benzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[OH:22].C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>C(#N)C>[CH3:29][O:30][C:31](=[O:34])[CH2:32][O:22][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[N:7]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH:6]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(O)c3cc(Br)ccc32)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cn(S(=O)(=O)c2ccc(OC)cc2)c2ccc(Br)cc12
Temperature: 80 °C
Yield: 46.6 %

Procedure:
To a stirring solution of 5-bromo-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-ol (21, 130 mg, 0.340 mmol) in acetonitrile (3.5 mL) in a high pressure reaction vessel was added potassium carbonate (235 mg, 1.70 mmol) and bromoacetic acid methyl ester (38.6 μL, 0.408 mmol). The vessel was flushed with a nitrogen atmosphere, sealed with a Teflon stopcock and heated to 80° C. for overnight. After the reaction mixture was cooled to 25° C., ethyl acetate was added and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain a light brown solid. Purification of the crude material was carried out using biotage chromatography (30% ethyl acetate in hexanes) which afforded the product as an off-white solid (22, 72.0 mg, 47% yield). MS(ESI) [M+H+]+=454.2; 456.2.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.N12CCCN=C1CCCCC2.[CH:23]([S:26](Cl)(=[O:28])=[O:27])([CH3:25])[CH3:24]>ClCCl>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[NH:2][S:26]([CH:23]([CH3:25])[CH3:24])(=[O:28])=[O:27]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Yield: 164.3 %

Procedure:
2-Aminoindan hydrochloride (5.16 g, 30 mmol, Sigma-Aldrich Company Ltd) was suspended in dry dichloromethane (100 ml), and cooled with stirring under argon to 0° C. To the suspension was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3 eq., about 14 ml, about 90 mmol) followed by the dropwise addition of isopropylsulfonyl chloride (6.8 ml, 60 mmol). The cooling bath was removed and the mixture stirred at room temperature for 1 h. The reaction mixture was washed with 1 M hydrochloric acid (2×50 ml). The organic layer was separated, dried over sodium sulphate and evaporated in vacuo (ie under reduced pressure) to give a yellow oil (11.8 g). The crude product was purified by chromatography on a 50 g Isolute™ Flash silica-gel column eluting from 20-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (6.88 g, 96%).