Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[N:2].[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8][C:7]=2[CH:6]=[CH:5][C:4]=1[S:16]([NH:19][C@H:20]([C:28]([OH:30])=O)[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])(=[O:18])=[O:17].C(OCC)C.S(Cl)([Cl:38])=O>>[N:1]#[N:2].[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8][C:7]=2[CH:6]=[CH:5][C:4]=1[S:16]([NH:19][C@H:20]([C:28]([Cl:38])=[O:30])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])(=[O:18])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2sc3ccccc3c2c1)C(=O)O
Agent: N#N
Solvent: CCOCC
Product: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2sc3ccccc3c2c1)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4.21 g of N2 -(2-dibenzothienylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2 -(2-dibenzothienylsulfonyl)-L-arginyl chloride.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH3:12])[CH2:5][CH2:4]1.[C:29]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39][CH2:38]2)=[N:35][CH:36]=1)#[N:30]>>[F:28][C:2]([F:1])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:43]([CH:40]3[CH2:39][CH2:38][N:37]([C:34]4[CH:33]=[CH:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=4)[CH2:42][CH2:41]3)=[O:44])[CH2:14]2)[CH3:12])[CH2:5][CH2:4]1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Reactant: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester was prepared from [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 652.3 [M]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:66])[C@H:10]([CH2:62][CH:63]([CH3:65])[CH3:64])[NH:11][C:12](=[O:61])[C@H:13]([C:57]([CH3:60])([CH3:59])[CH3:58])[NH:14][C:15](=[O:56])[C@H:16]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:55])[NH:17][C:18](=[O:47])[C@H:19]([CH2:38][CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH:20]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:66])[C@H:10]([CH2:62][CH:63]([CH3:64])[CH3:65])[NH:11][C:12](=[O:61])[C@H:13]([C:57]([CH3:59])([CH3:58])[CH3:60])[NH:14][C:15](=[O:56])[C@H:16]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:55])[NH:17][C:18](=[O:47])[C@H:19]([CH2:38][CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccccc1C[C@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C

Procedure:
A solution of 10.89 g (12.07 mmol) of N-[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 30 ml of piperidine and 120 ml of dichloromethane was stirred for 30 minutes at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly 20% ethyl acetate in hexane and then 10% methanol in dichloromethane for the elution. Evaporation gave N-[N-[N-[O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in the form of an oil which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Reaction time: 0.5 h
Yield: 121.8 %

Procedure:
Piperazine (107.5 g, 1.25 mole) was dissolved in DCM (500 ml). Trityl chloride (69.7 g, 0.25 mole) was added to the mixture cooled in an ice bath. After addition, the mixture was kept at room temperature for 30 min. The mixture was washed with water (500 ml, three times). And the organic layer was separated and dried over sodium sulfate. The mixture was concentrated to ca. 100 ml and added to hexane (1 liter). The solid was removed by filtration. The filtrate was evaporated to dryness to give a white solid (ca. 100 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[CH2:8][CH:9]1[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:35](Cl)(=[O:38])[O:36][CH3:37]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[CH2:8][CH:9]1[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]1[C:35]([O:36][CH3:37])=[O:38])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C1CCNC(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
Methyl 2-(3,5-di-tert-butylbenzyl)piperidine-4-carboxylate (3.691 g, 10.68 mmol) was dissolved in DCM (80 mL) and DIPEA (2.233 mL, 12.82 mmol) added followed by methyl carbonochloridate (1.262 mL, 16.02 mmol). The solution was stirred at room temperature for 1.5 h. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(3,5-di-tert-butylbenzyl)piperidine-1,4-dicarboxylate (3.91 g, 91%) as a yellow oil. MS m/z 404 (M+H)+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[NH:15][C:16](=[O:25])[C:17]([C:20]([O:22]CC)=[O:21])=[CH:18][N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+:27]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([O-:25])[C:17]([C:20]([O-:22])=[O:21])=[CH:18][N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Na+:27].[Na+:27]
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1[O-]
Temperature: 105 °C
Yield: 132 %

Procedure:
The mixture of ethyl 2-((4-morpholinophenyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (210 mg, 0.610 mmol) and sodium hydroxide (1M) were heated at 105° C. for 4 hours followed by heating at 40° C. overnight. Then the solution was condensed to recover the final product (290 mg, 132% yield). 1H-NMR confirmed the product.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][CH:32]=[CH:31]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ClCCCOc1ccc2[nH]ccc2c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Fc1ccc2c(C3CCN(CCCOc4ccc5[nH]ccc5c4)CC3)noc2c1
Yield: 123.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.6 g, 11.8 mmol), K2CO3 (1.6 g, 11.6 mmol), KI (200 mg), 5-(3-chloropropoxy)indole (2.2 g, 10.5 mmol) and Ch3CN (100 ml) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed 2 times with H2O, 2 times with brine and after drying with MgSO4 the solvent was removed in vacuo to yield 5.1 g of a dark oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500, using 2 silica gel columns and 4% MeOH-CH2Cl2 as eluent) to afford 2.65 g (65%) of a beige solid. Recrystallization from ethanol gave 2.2 g (54%) of a beige powder, m.p.=118°-121° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH:12]1([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH:12]1([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:2]3[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=3)[CH2:17][CH2:16]2)[CH2:14][CH2:13]1
Reactant: C1CNCCN(C2CC2)C1
Reactant: COC(=O)c1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCCN(C3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.16 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of 1-cyclopropyl-1,4-diazepane (247 mg, 1.16 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) in dichloromethane (4.00 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-cyclopropyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (312 mg, 97%) as a cream solid. This was used directly with no further purification.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH:33]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:39]3[CH2:40][CH2:41][N:36]([CH:33]4[CH2:35][CH2:34]4)[CH2:37][CH2:38]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCN(C3CC3)CC2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and 1-cyclopropylpiperazine to afford an off-white powder. UPLC-MS (Condition 3) tR=0.84 min, m/z=489 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.22-0.45 (m, 4H) 1.56-1.66 (m, 1H) 2.56 (br. s, 4H) 3.12 (br. s, 4H) 6.67 (br. s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.79-7.91 (m, 3H) 8.32 (br. s, 1H) 8.72 (s, 1H) 10.39 (br. s, 1H) 12.98-13.19 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=O)=[O:4].[SH2:11]>C(O)C.Cl>[CH3:1][N:2]1[S:11][C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:3]1=[O:4]
Reactant: S
Reactant: CNC(=O)C1CCCC1=O
Agent: Cl
Solvent: CCO
Product: Cn1sc2c(c1=O)CCC2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
5 g of 2-(N-methylcarbamoyl)cyclopentanone are dissolved in 100 cc of anhydrous ethanol saturated by anhydrous HCl gas. Into this solution, cooled to 0° C., there is passed for 5 hours a current of H2S and HCl gas. After having de-gassed the reaction mixture, there is added, with agitation, 0.5 molar equivalent of sodium metaperiodate fixed on acidic alumina (Al2O3), the temperature being maintained at 0° C. One-half hour later the reaction mixture is filtered. The filtrate is concentrated under reduced pressure. The residue is taken up in a 1:1 mixture of ethyl acetate and water. The pH of the aqueous solution is then adjusted, with agitation, to about 6 by the addition of sodium bicarbonate. The aqueous phase is decanted, then extracted with chloroform. The chloroform phase is then dried on sodium sulfate, and concentrated. On evaporation, an amorphous white solid, melting at 111° C. is obtained. Mass spectroscopy gives the expected relative peak at m/e: 155 (C7H9NOS)
Reaction SMILES: Cl[SiH2:2][Cl:3].[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[NH:6]1.C(N(CC)CC)C.Cl>CCCCCC>[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[N:6]1[SiH2:2][Cl:3]
Reactant: CC1CCCC(C)N1
Reactant: Cl[SiH2]Cl
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1CCCC(C)N1[SiH2]Cl
Temperature: -20 °C
Yield: 66 %

Procedure:
In a 2000 ml 3-necked round bottom flask equipped with mechanical stirror and an addition funnel, 1000 ml hexane was added. With the flask was cooled to −20° C. using a dry ice IPA cold bath, 101 g (1.0 mol) dichlorosilane was condensed and dissolved into hexane. With stirring, a mixture of 113 g (1.0 mol) 2,6-dimethylpiperidine and 111 g (1.1 mol) triethylamine was added dropwise to the flask. After the addition was complete, the reaction mixture was stirred at −20° C. for 1 hour, and then let warming up to room temperature. A salt byproduct precipitate of HCl.Et3N was removed by vacuum filtration in a glove bag purging with N2 to prevent the product reacting with the moisture in the air. A GC/MS analysis on the filtrate confirmed the product 2,6-dimethylpiperidinochlorosilane, showing the product with a molecular ion mass of 177 and supporting mass fragment of mass M —CH3 of 162. The solvent hexane was removed by distillation and the product was separated by vacuum distillation. The boiling point was 60° C. at 10 torr. The yield was 66%.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:24][CH:23]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][N:38]1[CH2:37][CH2:36][N:35]([C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:34][CH:33]=2)[CH2:40][CH2:39]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCBr)Nc1ccccc1Cc1ccccc1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: O=C(CCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (11) synthesized in Reference Example 11 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.B(O)(O)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH2:44])=[O:43])[CH:37]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:36]2[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=2)[C:42]([NH2:44])=[O:43])=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C(N)=O)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and (3-aminocarbonyl)phenylboronic acid (58 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (49 mg, yield 100%).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]2[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]2)=[CH:10][CH:9]=1)[C:3]#[N:4].N.[H][H]>CO.[Ni]>[CH3:21][C:18]1([CH3:22])[O:17][C@H:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][CH:2]([NH2:1])[CH2:3][NH2:4])=[CH:9][CH:10]=2)[CH2:20][O:19]1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC(N)C#N)cc2)O1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC1(C)OC[C@@H](COc2ccc(CCCC(N)CN)cc2)O1

Procedure:
A solution of 2-amino-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-pentanenitrile (1.7 g, 4.28 mmol) in a 2M ammonia in methanol solution (50 ml) is passed through a H-CUBE apparatus fitted with a Raney nickel CatCart at 50° C. and a hydrogen pressure of 50 bar and a flow rate of 1.5 ml/min. After 5 hours of continuous cycling of the solution the reaction mixture is concentrated in vacuo to give 5-[4-((R)-2,2-Dimethyl-[1,3]dioxolane-4-ylmethoxy)-phenyl]-pentane-1,2-diamine as a light-yellow oil; [M+H]+ 309
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:8]1[CH2:11][C:10]([C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)([F:12])[CH2:9]1)([CH3:7])[CH3:6])C.[BH4-].[Na+]>>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([C:10]4([F:12])[CH2:9][N:8]([C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])[CH2:11]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CCOC(=O)C(C)(C)N1CC(F)(c2nc3c(N4CCOCC4)nc(-n4c(CC)nc5ccccc54)nc3n2C)C1
Agent: [BH4-]
Agent: [Na+]
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CN(C(C)(C)CO)C3)n(C)c2n1
Reaction time: 3 h
Yield: 56.2 %

Procedure:
To a solution of 2-{3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-fluoroazetidin-1-yl}-2-methylpropionic acid ethyl ester (40 mg, 0.07 mmol) in IMS (4 mL) was added NaBH4 (28 mg, 0.73 mmol) and the resulting mixture stirred at r.t for 3 h. Further NaBH4 (28 mg, 0.73 mmol) was added and the mixture stirred for a further 18 h. The reaction mixture was quenched with H2O, extracted with EtOAc and the organic phase dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) then dissolved in a mixture of MeCN and H2O and allowed to freeze-dry affording 850 as a white solid (20 mg, 54%). LCMS (method I): RT 2.64 min, [M+H]+ 509.4. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 4.58-4.49 (1 H, m), 4.44-4.14 (4 H, brd m), 4.08 (2 H, dd, J=18.70, 9.19 Hz), 3.81-3.74 (9 H, m), 3.28-3.26 (2 H, m), 3.19 (2 H, d, J=5.40 Hz), 1.34 (3 H, t, J=7.43 Hz), 0.91 (6 H, s)
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:19][C@@H:18]([O:20][CH2:21][CH2:22]OS(C)(=O)=O)[C@H:17]([OH:28])[CH2:16]2)[N:10]=1>O>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:16][C@H:17]3[O:28][CH2:22][CH2:21][O:20][C@@H:18]3[CH2:19]2)[N:10]=1
Reactant: CS(=O)(=O)OCCO[C@@H]1CN(c2cccc(Br)n2)C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(N2C[C@H]3OCCO[C@@H]3C2)n1

Procedure:
1.49 g of 60% oily sodium hydride was added little by little to a solution of 150 ml of N,N-dimethylformamide containing 11.82 g of 2-bromo-6-[(3R,4R)-3-hydroxy-4-(2-methanesulfonyloxyethyl)oxypyrrolidine-1-yl]pyridine under stirring in an ice bath. Then, after stirring at room temperature for one hour, 372 mg of 60% oily sodium hydride was added thereto. After stirred for further 45 minutes, the reaction mixture was poured into water and extracted twice with ethyl acetate. The organic phase was washed with water and brine, and the solvent was removed. The residue was crystallized from ethyl acetate/hexane, to give 5.35 g of the target compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH2:30]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([NH:30][CH3:29])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (4.70 g, 11.9 mmol) in ethanol (80 ml) was treated with methylamine (33% w/v in ethanol, 12.0 ml, 96.0 mmol) and the solution was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (9:1) gradually changing to dichloromethane:ethyl acetate (8:2) to afford the title compound as a pale yellow oil which crystallised on standing (4.23 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19](Cl)=[C:18]([F:23])[CH:17]=2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[Cl:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[Cl:43]C(Cl)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2([Cl:43])[CH:21]=[CH:20][CH:19]=[C:18]([F:23])[CH2:17]2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[Cl:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1Cl
Reactant: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(C2(Cl)C=CC=C(F)C2)c(F)c(NC(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Methyl 4-(bis(tert-butoxycarbonyl)amino)-3-chloro-6-(4-chloro-3-fluorophenyl)-5-fluoropicolinate (2.1 g, 3.94 mmol) was dissolved in dichloroethane (20 mL) and trifluoroacetic acid (0.598 mL, 7.76 mmol) was added at rt. The reaction mixture was stirred overnight at room temperature then concentrated under vacuum. The product was purified by flash chromatography (SiO2, eluting with 2-20% ethyl acetate in dichloromethane) to provide the title compound as a white solid (1.64 g, 98%): 1H NMR (300 MHz, CDCl3) δ 7.80 (dd, J=22.0, 8.5 Hz, 2H), 7.50 (dd, J=8.3, 7.6 Hz, 1H), 6.51 (s, 1H), 4.02 (s, 3H), 1.56 (s, 9H); ESIMS m/z 431 ([M−H]−).