Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:10]2[C@H:5]([CH2:6][CH2:7][C@@H:8]([NH:11][C:12]3[C:13]4[CH:20]=[CH:19][N:18]([S:21]([C:24]5[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH2:9]2)[CH2:4][C@@H:3]1[NH:31]C(=O)OC(C)(C)C.Cl>CO.O1CCOCC1>[NH2:31][C@@H:3]1[C:2](=[O:1])[N:10]2[C@H:5]([CH2:6][CH2:7][C@@H:8]([NH:11][C:12]3[C:13]4[CH:20]=[CH:19][N:18]([S:21]([C:24]5[CH:25]=[CH:26][C:27]([CH3:28])=[CH:29][CH:30]=5)(=[O:23])=[O:22])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH2:9]2)[CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](NC(=O)OC(C)(C)C)C(=O)N5C4)ncnc32)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](N)C(=O)N5C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of tert-butyl (2S,6R,8aR)-3-oxo-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-octahydroindolizin-2-ylcarbamate 127.4 (550 mg (1.02 mmole) in MeOH (21 mL) was treated with of 4 M HCl in 1,4-dioxane (4.0 mL (20.3 mmol) and stirred at room temperature for 23 hr. The mixture was concentrated to dryness, and the residue was dissolved in MeOH (20 ml) and treated with polymer-supported carbonate resin (1.2 g, 3.5 mmol/g). The suspension was stirred at room temperature for 1 hour. The resin was removed by filtration through a celite plug, and the filtrate was concentrated in vacuo to yield 414 mg of (2S,6R,8aR)-2-amino-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one 127.5 as pale yellow solid that was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.42 (s, 1H), 8.04 (d, J=8.3 Hz, 2H), 7.43 (d, J=4.0 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 6.49 (d, J=3.8 Hz, 1H), 5.64-5.46 (m, 1H), 4.41 (br. s., 1H), 4.22 (d, J=14.1 Hz, 1H), 3.72-3.54 (m, 2H), 3.08 (dd, J=3.1, 13.9 Hz, 1H), 2.38 (s, 3H), 2.10 (ddd, 0.1=4.3, 8.7, 13.3 Hz, 1H), 2.04-1.91 (m, 1H), 1.90-1.61 (m, 4H), 1.47 (dd, J=2.9, 11.9 Hz, 1H); LCMS (ESI) m/z: 441.2 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH:12]C(OC(C)(C)C)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:6]([OH:20])=[O:5]
Reactant: CC(C)(C)OC(=O)CCOCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: NCCOCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(2-tert-Butoxycarbonylamino-ethoxy)-propionic acid tert-butyl ester (10 g) was dissolved in a 1:1 trifluoroacetic acid (TFA)/DCM mixture (100 mL) and stirred at room temperature for 1 h. The solvent was then removed on a rotary evaporator and the resulting oil was re-dissolved in DCM and concentrated to dryness. This process was repeated until minimal TFA scent remained before the oil was dried on high vacuum for several hours.
Reaction SMILES: [I:1][C:2]1[C:3]([O:25][CH3:26])=[C:4]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14](I)[C:13]=2[O:23][CH3:24])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:27]([Li])CCC.CI>C1COCC1.[Cl-].[NH4+]>[CH3:26][O:25][C:3]1[C:2]([I:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([CH3:27])[C:13]=1[O:23][CH3:24]
Reactant: COc1c(I)cc2ccccc2c1-c1c(OC)c(I)cc2ccccc12
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1c(C)cc2ccccc2c1-c1c(OC)c(I)cc2ccccc12
Temperature: 25 °C

Procedure:
To a −80° C. solution of (+/−)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl (2.016 g, 3.6 mmol) in THF (dry, distilled, 80 mL, 0.044 M) was added n-butyl lithium (2.8 mL, 3.9 mmol) dropwise. The reaction mixture turned yellow and was stirred for 1 h before the addition of methyl iodide (dry, distilled, 0.35 mL, 5.6 mmol). The reaction mixture was allowed to gradually warm to room temperature. After stirring for a further 3 h saturated aqueous ammonium chloride solution (4 drops) was added. The reaction mixture was evaporated to dryness, the residue taken up in diethyl ether and washed with water. The organic layer was dried (MgSO4), filtered and the filtrate evaporated to dryness to give a pale yellow solid. Purification of the crude material by flash column chromatography (4% ethyl acetate/hexane) yielded (+/−)-2,2′-dimethoxy-3-iodo-3′-methyl-1,1′-binaphthyl.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C:9]=3[C:21](=[O:23])[O:22][C:4]=2[CH:3]=1.Cl[C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][C:8]3[C:5]4[CH:6]=[CH:7][C:2]([O:1][C:25]5[N:29]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)[N:28]=[N:27][N:26]=5)=[CH:3][C:4]=4[O:22][C:21](=[O:23])[C:9]=3[CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: O=c1oc2cc(O)ccc2c2c1CN(Cc1ccccc1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1oc2cc(Oc3nnnn3-c3ccccc3)ccc2c2c1CN(Cc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8-hydroxy-3(phenylmethyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (15 g, 0.049 moles), 5-chloro-1-phenyl-1H-tetrazole (9 g, 0.0498 moles), and potassium carbonate (30 g) in dimethylformamide (250 ml) is heated at 85°-95° C. for 5 hours. The reaction mixture is cooled and poured over ice water. The aqueous mixture is allowed to stand at room temperature overnight. The solid is filtered off and washed with water. Recrystallization from ethyl acetate gave the product (10.14 g), mp 165°-166° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([O:17][CH3:18])[C:13]([F:19])=[CH:12][N:11]=1.FC(F)(F)C(O)=O.[NH2:27][C:28]1[C:29]2[C:30]3[C:31](=[N:43][NH:44][N:45]=2)[CH:32]=[C:33]([CH2:38][C:39]([NH:41][CH3:42])=[O:40])[C:34]=3[CH2:35][S:36][N:37]=1>CN(C)C=O>[NH2:27][C:28]1[C:29]2[C:30]3[C:31](=[N:43][N:44]([CH2:9][C:10]4[C:15]([CH3:16])=[C:14]([O:17][CH3:18])[C:13]([F:19])=[CH:12][N:11]=4)[N:45]=2)[CH:32]=[C:33]([CH2:38][C:39]([NH:41][CH3:42])=[O:40])[C:34]=3[CH2:35][S:36][N:37]=1
Reactant: CNC(=O)Cc1cc2n[nH]nc3c-2c1CSN=C3N
Reactant: COc1c(F)cnc(CCl)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)Cc1cc2nn(Cc3ncc(F)c(OC)c3C)nc3c-2c1CSN=C3N
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 45.4 %

Procedure:
Potassium carbonate (85 mg) and 2-(chloromethyl)-5-fluoro-4-methoxy-3-methylpyridine hydrochloride (52 mg) were added to an N,N-dimethylformamide (5 ml) solution of 2-(4-amino-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl)-N-methylacetamide trifluoroacetate (60 mg). The resulting mixture was stirred at 50° C. for 3.5 hours. Thereafter, insoluble matter was removed by filtration, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol), so as to obtain the title compound (30 mg) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].Br[CH2:28][CH2:29][CH2:30]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([O:3][C:4]([C:5]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:30][CH2:29][CH2:28][N:11]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:26])[CH3:2]
Reactant: BrCCCBr
Reactant: CCOC(=O)C(Nc1ccc(Oc2ccc(I)cc2)nc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(I)cc2)nc1
Temperature: 55 °C
Yield: 71.8 %

Procedure:
2-[6-(4-Iodo-phenoxy)-pyridin-3-ylamino]-malonic acid diethyl ester (4.35 grams, 9.25 mmol) was added to a flame dried flask and dissolved in dimethylformamide (90 mL). 1,3 dibromopropane (938 μL, 9.25 mmol) and cesium carbonate (6 grams, 18.5 mmol) were added and the reaction mixture was stirred for approximately 24 hours to 48 hours. The solution was filtered through celite, and then concentrated under vacuum while heating to 55° C. to remove the dimethylformamide (azeotroping with toluene). The crude product obtained was chromatographed on silica gel (ISCO MPLC purification, 40 minutes, 0-50% ethyl acetate gradient, Biotage flash 40 m column) to provide 3.39 grams (72%) of the title compound. MS m/z: ESI+ 511.1 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][CH:13]=1)C>C1COCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][CH:13]=[C:12]([CH2:11][CH2:10][OH:9])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)Cc1coc2ccc(Cl)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1coc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(5-chloro-1-benzofuran-3-yl)acetate (1.19 g, 50 mmol) in THF (20 mL) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4, filtered and concentrated. The product, 2-(5-chloro-1-benzofuran-3-yl)ethanol, was obtained as a white oil and was pure enough and be taken to the next step without purification. Yield: 850 mg (86%); (M+H): 197.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH3:43])=[O:41]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH3:43])=[O:41])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC)cc1)n2C)c1ccccc1
Yield: 41 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and methyl chloroformate. Yield: 41% of theory, C30H32N6O5 (556.6); Rf value: 0.85 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=557; (M+H+Na)++=290; (M+Na)+=579.
Reaction SMILES: C[N:2](C)/[CH:3]=[C:4](\[CH3:10])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:12]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][N:15]=1)N>CC(O)=O.CCO>[C:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:12][NH:2]/[CH:3]=[C:4](\[CH3:10])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:19]=1)#[N:21]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)/C(C)=C/N(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)/C(C)=C/NNc1cc(C#N)ccn1
Temperature: 90 °C
Yield: 62.1 %

Procedure:
A solution of ethyl(E)-3-(dimethylamino)-2-methylprop-2-enoate (668 mg, 4.25 mmol) and 2-hydrazinylpyridine-4-carbonitrile (570 mg, 4.25 mmol, PREPARATION 2) in 2 mL HOAc and 10 mL EtOH was charged to a flask and the mixture was heated to 90° C. for 30 min. Cooled to room temperature and removed the solvent. The residue was dissolved in ethylacetate and water, aqueous basified with NaHCO3 sat (pH=8), extracted with ethylacetate. The organic phase was washed with brine and dried with anhydrous sodium sulfate and then purified by silica gel chromatograph to give 0.65 g of the title compound (62%). [M+H] Calc'd for C12H14N4O2, 247; Found, 247.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](S(C)(=O)=O)[N:14]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1nccc(-c2[nH]c(-c3ccccc3)nc2-c2ccc(F)cc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Product: Fc1ccc(-c2nc(-c3ccccc3)[nH]c2-c2ccncn2)cc1
Reaction time: 8 h

Procedure:
To a suspension of 4-(4-(4-fluorophenyl)-2-phenyl-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidine, 76 (0.50 g) in ethanol (20 mL) was added in portions, sodium borohydride (0.28 g). After stirring overnight, hydrochloric acid (20 mL, 0.5 M) is added and the solution is allowed to stir for 30 min, whereupon, the solution is neutralized with saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane. The combined organic phases are washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue is then subjected to chromatography, furnishing the title compound, 77 (0.29 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:24][C:25]1(OCC)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:23]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:25]3([O:24][CH2:22][CH3:23])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCOC1(OCC)CCCCCCCCCCC1
Product: CCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCCCCCCC1
Yield: 29.2 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-diethoxycyclododecane (2.56 g, 00 mmol) in the same manner as the example 20 to give the compound 33 (162 mg, 29%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8](=[O:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@@H:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(=O)c1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](O)C[C@H](O)COC(=O)c1ccccc1
Temperature: 50 °C
Yield: 82.3 %

Procedure:
To (S)-6-benzoyloxy-3-oxo-5-hydroxyhexanoic acid tert-butylester (161 mg, 0.50 mmol) and RuBr2(S)-BINAP (4.4 mg, 0.0050 mmol) (BINAP was 2,2′-bisdiphenylphosphino-1,1′-binaphthyl), 2 mL of a methanol-water (10/1) solution was added to completely dissolve the (S)-6-benzoyloxy-3-oxo-5-hydroxyhexanoic acid tert-butylester and RuBr2(S)-BINAP in an argon atmosphere. Hydrogen replacement at −78° C. was performed three times. After the temperature of the resulting mixture had increased to 50° C., the mixture was allowed to react for twenty hours under a hydrogen pressure of 5.0 kg/cm2. After extraction of hydrogen, the mixture was condensed and purified by silica gel column chromatography. As a result, 133.4 mg (82%) of (3S, 5S)-6-benzoyloxy-3,5-dihydroxyhexanoic acid tert-butylester was obtained. The diastereomer ratio determined by high performance liquid chromatography (HPLC) analysis was (3R, 5S):(3S, 5S)=10.4/89.6.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[Si]([C:32]([F:35])([F:34])[F:33])(C)(C)C.Cl>C1COCC1>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]([OH:25])[C:32]([F:35])([F:34])[F:33])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
Tetrabutylammonium fluoride (0.1 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 4-methyl-benzaldehyde (1.2 g, 10 mmol) and TMSCF3 (1.8 ml, 12 mmol) in 10 ml THF at 0° C. The formed mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of 1N HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 1.6 g of 1-(4-methylphenyl)-2,2,2-trifluoro-ethanol, yield 86%.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][Cl:8])(=[O:3])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.C(O)(C)C>CC(C)=O>[C:1]([O:4][CH2:5][C:6](=[O:9])[CH2:7][Cl:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(O)CCl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)CCl
Yield: 59.6 %

Procedure:
To a solution of 1-acetoxy-3-chloro-2-propanol (15.3 g) in acetone (250 ml) is dropwise added Jones reagent (37.4 ml) containing chromic anhydride (10.39 g) and conc. sulfuric acid (10.18 ml) in 1 hour, and the resultant mixture is stirred at room temperature for 3 hours. The reaction mixture is mixed with isopropanol (10 ml) and the insoluble material is filtered off. The organic layer is concentrated in vacuum, and the residue is distilled to give 1-acetoxy-3-chloro-2-propanone (9 g) as an oil boiling at 102°-104° C./15 mm Hg. The yield is 60.0%.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=1[Br:25])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>CCO.CCOC(C)=O.[Pt]>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Br:25])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a solution of (S)-2-(2-Bromo-6-methyl-4-nitrophenyl)-2-tert-butoxyethyl pivalate (9 g, 0.022 mol) in EtOH (50 mL) and EtOAc (50 mL) was added Pt/C (1.4 g), and the reaction was fitted with a balloon of H2. The reaction mixture was stirred at room temperature for 3 h. TLC showed the reaction was complete. The reaction mixture was filtered over Celite. The filtrate was concentrated in vacuo to give (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (7 g, 82%) as brown oil, which was immediately used for next step without further purification. 1H-NMR: 400 MHz, (CDCl3) δ: 6.70 (s, 1H), 6.40 (s, 1H), 5.38 (app. s, broad, 1H), 4.22 (app. s, broad, 1H), 4.05 (app. s, broad, 1H), 3.60 (app. s, broad, 2H), 2.47 (s, 3H), 1.17 (s, 9H), 1.13 (s, 9H).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH2:10])[CH2:3]2.CN1CCCN(C)P1.F[C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([NH:27][CH3:28])=[O:26]>CS(C)=O>[CH3:28][NH:27][C:25](=[O:26])[C:24]1[CH:29]=[C:20]([NH:10][CH:4]2[CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)[CH:21]=[CH:22][C:23]=1[N+:30]([O-:32])=[O:31]
Reactant: NC1CN2CCC1CC2
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: CN1CCCN(C)P1
Agent: Cl
Solvent: CS(C)=O
Product: CNC(=O)c1cc(NC2CN3CCC2CC3)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 26.9 %

Procedure:
To a mixture of quinuclidin-3-amine hydrochloride (1.06 g, 5.30 mmol) and polymer supported dimethylperhydro-1,3,2-diazaphosphorine (7.0 g, 15.4 mmol) in DMSO (50 mL) was added 5-fluoro-N-methyl-2-nitrobenzamide (Intermediate 3A) (1 g, 5.05 mmol) and reaction heated at 60° C. for 72 hours. The resin was removed by filtration and washed thoroughly with methanol and dichloromethane. The filtrate was purified using a 20 g SCX cartridge followed by trituration with dichloromethane/methanol/diethyl ether to afford N-methyl-2-nitro-5-(quinuclidin-3-ylamino)benzamide (0.41 g, 1.36 mmol).
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[CH2:3][NH:4]C(=O)OC(C)(C)C.ClS([N:26]=[C:27]=[O:28])(=O)=O.O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:27](=[O:28])([O:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:20])[F:21])[CH2:3][NH2:4])[NH2:26]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NCC(OC(N)=O)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A solution of 420 mg (1.38 mmol) of the compound of Example 36A in 100 ml of acetonitrile was cooled to −15° C., and a solution of 168 μl (1.93 mmol) of chlorosulphonyl isocyanate in 10 ml of acetonitrile was added dropwise. After 5 min, 50 ml of water were added and the reaction mixture was stirred further at 60° C. overnight. After cooling to RT, 50 ml of a saturated aqueous sodium bicarbonate solution were added. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue (321 mg, about 90% pure, 85% of theory) corresponded to the title compound and was reacted further without additional purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[F:8].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([Cl:16])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)/C=C/c1ccc(F)c(F)c1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
A stirred mixture of (E)-3-(3,4-difluorophenyl)-2-propenoic acid (8.2 kg), toluene (7.4 kg) and pyridine (0.18 kg) was heated to 65° C. and then thionyl chloride (7.4 kg) was added over 30 minutes. The reaction was stirred for a further 2 h 15 minutes after the addition was complete, then diluted with toluene (8.7 kg). Excess thionyl chloride, sulfur dioxide and hydrogen chloride were then distilled out, together with toluene (10 L), under reduced pressure, yielding a solution of the (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride (approximately 9 kg) in toluene.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][C:23]=3[Cl:24])[NH:20][CH:19]=[C:18]4[CH:25]=[O:26])=[CH:11][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].Cl([O-])=[O:28].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O.CC(=CC)C>[C:1]([N:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][C:23]=3[Cl:24])[NH:20][CH:19]=[C:18]4[C:25]([OH:28])=[O:26])=[CH:13][CH:14]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CC(=O)N1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
To a solution of 5-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde (60 mg, 0.163 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) was added 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (164 mg, 1.8 mmol) and sodium phosphate monobasic dihydrate (381 mg, 2.445 mmol) in water (1.5 mL). The reaction mixture was stirred for 2 hours at room temperature and treated with additional sodium chlorite (218 mg, 2.4 mmol) and sodium phosphate monobasic dihydrate (509 g, 3.26 mmol) in water (1.5 mL) and 2-methyl-2-butene (0.5 mL). The resulting mixture was stirred at room temperature for an additional 16 h. The reaction mixture was evaporated in vacuo and the aqueous residue was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DMSO and purified via prep-HPLC to give 5-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carboxylic acid (25 mg) as a white solid. MS (ES+) 383.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.96 (br, 1 H), 8.08 (d, 1 H), 7.93 (s, 1 H), 7.64 (s, 1 H), 7.38 (m, 4 H), 3.1-3.9 (m, 5 H), 2.2-2.5 (m, 1 H), 1.9-2.1 (m, 4 H).