Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(CC)C(C)C)(C)C.[N:14]([CH2:17][CH:18]([S:32][S:33][CH3:34])[CH2:19][C@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([OH:23])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[C:3]([CH2:2][O:23][C:21](=[O:22])[C@@H:20]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:19][CH:18]([S:32][S:33][CH3:34])[CH2:17][N:14]=[N+:15]=[N-:16])#[N:4]
Reactant: CSSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
Bromoacetonitrile (45 μl, 0.669 mmol) and N,N-diisopropylethylamine (58 μl, 0.334 mmol) were added to a solution of (S)-5-azido-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid (Compound 35) (75 mg, 0.223 mmol) in acetonitrile (2 ml), and the reaction solution was stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate/saturated ammonium chloride, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-5-azido-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid cyanomethyl ester (Compound 36) (81 mg, 97%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.Br[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:16]1[CH:22]=[CH:21][CH:20]=[C:18]([NH2:19])[CH:17]=1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccccc2OC(F)(F)F)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
2-trifluoromethoxyphenylboronic acid (0.143 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-5% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.086 g in 74% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][CH2:2][C:3]1([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Product: CC(=O)NCC1(N2CCN(C)CC2)CCCCC1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
1-[1-(Aminomethyl)cyclohexyl]-4-methyl piperazine (10.57 g.,) was added slowly to stirred acetic anhydride (40 ml) cooled in ice and the stirring was continued for 15 mins. The mixture was heated under reflux for 1 hr.. The solution was evaporated to dryness and re-evaporated with ethanol/benzene (X2). The residue was dissolved in water the solution made alkaline with 5NNaOH (pH = 14), extracted with chloroform (X3), dried (anhyd.Na2SO4) and evaporated. The residue was dissolved in hot petroleum ether (80°-100° ) decolourised with charcoal and allowed to cool. The crystalline solid which formed was recrystallised from petroleum ether (b.p. 80°-100° ) to give 1-[1-(acetamidometyl)cyclohexyl]-4-methyl piperazine (8.3 g; 65%) m.p. 110°-111°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[C:21]1([C@@H:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:29][C@H:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:28])=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: C[C@H](N)c1ccccc1
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCCN(CC(=O)N[C@@H](C)c1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and (1S)-1-phenylethanamine: MS (APCI) m/z 390 (M+1).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([N:15]1[CH2:109][CH2:108][CH2:107][C@H:16]1[C:17]([NH:19][C@H:20]([C:26]([NH:28][C@H:29]([C:40]([NH:42][C@H:43]([C:48]([NH:50][C@H:51]([C:62]([NH:64][CH2:65][C:66]([NH:68][C@H:69]([C:79]([NH:81][CH2:82][C:83]([NH:85][C@H:86]([C:97]([N:99]1[CH2:106][CH2:105][CH2:104][C@H:100]1[C:101]([NH2:103])=[O:102])=[O:98])[C@@H:87]([CH3:96])[O:88][CH2:89][C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1)=[O:84])=[O:80])[CH2:70][O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:67])=[O:63])[C@@H:52]([CH3:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[C@@H:30]([CH3:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])[CH2:21][CH2:22][C:23](=[O:25])[NH2:24])=[O:18])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:117]([C:136]([O:138][C:139]([CH3:142])([CH3:141])[CH3:140])=[O:137])[C@H:118]([C:124](OC1C=CC([N+]([O-])=O)=CC=1)=[O:125])[CH2:119][CH2:120][C:121](=[O:123])[NH2:122]>>[NH:117]([C:136]([O:138][C:139]([CH3:142])([CH3:141])[CH3:140])=[O:137])[C@H:118]([C:124]([NH:1][C@H:2]([C:13]([N:15]1[CH2:109][CH2:108][CH2:107][C@H:16]1[C:17]([NH:19][C@H:20]([C:26]([NH:28][C@H:29]([C:40]([NH:42][C@H:43]([C:48]([NH:50][C@H:51]([C:62]([NH:64][CH2:65][C:66]([NH:68][C@H:69]([C:79]([NH:81][CH2:82][C:83]([NH:85][C@H:86]([C:97]([N:99]1[CH2:106][CH2:105][CH2:104][C@H:100]1[C:101]([NH2:103])=[O:102])=[O:98])[C@@H:87]([CH3:96])[O:88][CH2:89][C:90]1[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=1)=[O:84])=[O:80])[CH2:70][O:71][CH2:72][C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)=[O:67])=[O:63])[C@@H:52]([CH3:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[C@@H:30]([CH3:39])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:27])[CH2:21][CH2:22][C:23](=[O:25])[NH2:24])=[O:18])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:125])[CH2:119][CH2:120][C:121](=[O:123])[NH2:122]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)[C@@H](C)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)[C@@H](C)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Yield: 95.8 %

Procedure:
By using 2.65 g of Boc-Thr(Bzl)-Pro-Gln-Thr(Bzl)-Asn-Thr(Bzl)-Gly-Ser(Bzl)-Gly-Thr(Bzl)-Pro-NH2 and 907 mg of Boc-Gln-ONp, and the same procedure as in Reference Example 18 was repeated to obtain 2.74 g (yield: 95.5%) of the above-mentioned objective product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]([F:21])([F:20])[CH2:16][C:17](=[O:19])[CH3:18]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]([OH:19])([CH2:16][C:15]([F:21])([F:20])[F:14])[CH3:18])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(=O)CC(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(CC(F)(F)F)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,4-dibromobenzene (2.5 g, 10.6 mmol) in THF (50 mL) at −78° C. was added n-BuLi (6.5 mL, 10.4 mmol; 1.6 M in hexanes) and the mixture was stirred at −78° C. for 15 min. 4,4,4-Trifluoro-2-butanone (1.3 g, 10.3 mmol) was then added. After further stirring for 15 min., the mixture was quenched with aqueous NH4Cl and extracted with Ethyl acetate. Purification by combi-flash chromatography (40 g column; eluted with hexanes—Ethyl acetate (10% -20%) in 20 min.; flow rate: 35 mL/min and collected 18 mL/fraction) yielded the title compound as a light brown liquid.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: C[C@H](O)C(=O)N1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=O)[CH2:11]Br)[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C1C=CC=CC=1.[Cl:23][C:24]([Cl:34])([Cl:33])[CH2:25][O:26][C:27]([NH:29][C:30]([NH2:32])=[S:31])=[O:28]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:32]=[C:30]([NH:29][C:27]([O:26][CH2:25][C:24]([Cl:33])([Cl:23])[Cl:34])=[O:28])[S:31][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Reactant: NC(=S)NC(=O)OCC(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=NOC)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1

Procedure:
To a solution of 2.2 g. of ethyl α-methoxyimino-β-oxo-γ-bromobutyrate in 40 ml. of ethanol are added 1.22 g. of dimethylaniline and 2.2 g. of N-(β,β,β-trichloroethoxycarbonyl)thiourea. The mixture is heated for 1.5 hours under reflux and concentrated under reduced pressure. The concentrate of the reaction mixture is recrystallized from ligroin to give ethyl α-methoxyimino-[2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-yl]acetate as crystals. 1.84 g. Melting point: 125°-128° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]([O-])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]([CH:12]1[CH2:13][CH2:14][N:15]([CH2:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])[CH2:16][CH2:17]1)[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: COc1ccncc1C(=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccncc1CN1CCC(N(C(=O)OC(C)(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 105.9 %

Procedure:
A solution of 4-(N-tert-butoxycarbonyl-N-isopropylamino)piperidine (118 g, 0.49 mol) in dichloroethane (600 mL) was stirred at room temperature for 1 hour, and then 4-methoxypyridine-3-carboxylate (63.5 g, 0.46 mol) was added. The resulting solution was stirred at room temperature for 2.5 hours and then cooled to 5° C. in an ice/water bath. Sodium triacetoxyborohydride (124 g, 0.58 mol) in dichloroethane (600 mL) was added and the reaction mixture was stirred at 5° C. for 15 minutes. The ice bath was then removed and reaction mixture was stirred for 4 hours at room temperature. Acetic acid (30 mL) was then added to the reaction mixture and the resulting mixture was stirred for 0.5 hours, and then concentrated to half its original volume. This solution was cooled in a dry ice/acetone bath and 10 N aqueous sodium hydroxide (350 mL) was added. This mixture was stirred for 0.5 hours and then the organic layer was separated and washed with 1 N aqueous sodium hydroxide (400 mL). The aqueous layer was then washed three times with dichloromethane (400 mL) and the combined organic layers were dried over sodium sulfate (40 g). The sodium sulfate was filtered off and washed with dichloromethane (100 mL) and the combined organic layers were concentrated in vacuo to give 177 g of the title intermediate as a yellow oil (>99% yield; 74% purity by GC).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:13]([NH:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1

Procedure:
reacting L-histidine with benzyl chloroformate, resulting in an Nα-carbobenzoxy-L-histidine;
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23](O)[CH2:24][CH3:25])=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:37])CCOC>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([F:37])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 15 h
Yield: 77 %

Procedure:
To a stirred suspension of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (82.1 mg, 0.200 mmol) in acetonitrile (1.0 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride at room temperature. After 15 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (63.8 mg, 0.155 mmol, 77%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][OH:13])=[N:8][CH:9]=1)([O-:3])=[O:2].Cl[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][O:13][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=[N+]([O-])c1cnc(NCCO)cn1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OCCNc1cnc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
A solution of 2-(5-nitro-pyrazin-2-ylamino)-ethanol (370 mg, 2.01 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was treated with chlorotriethylsilane (371 μL, 2.21 mmol) and imidazole (342 mg, 5.02 mmol). The reaction mixture was then allowed to warm up to 25° C. where it was stirred overnight for 16 h. After this time, the reaction was diluted with ethyl acetate (20 mL) and a saturated aqueous sodium chloride solution (10 mL) and then further extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) afforded (5-nitro-pyrazin-2-yl)-(2-triethylsilanyloxy-ethyl)-amine (531 mg, 89%) as a light yellow solid: (ES)+-HRMS m/e calcd for C12H22N4O3Si (M+H)+ 299.1534, found 299.1538.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[CH3:19][CH:20]([S-:22])[CH3:21].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:19][CH:20]([S:22][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)[CH3:21]
Reactant: CC(C)[S-]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
tert-Butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (Intermediate 239, 0.320 g, 1.15 mmol) and sodium 2-propanethiolate (0.147 g, 1.50 mmol) were combined in DMF (3 mL) and stirred at room temperature for 18 h. The mixture was then diluted with EtOAc (30 mL) and washed with water (3×10 mL). The organic layer was dried over sodium sulfate and concentrated to yield a yellow oil. This was purified by FCC, eluting with a gradient of 0-20% EtOAc in heptane to afford the title compound as a colourless oil (0.179 g, 60%). 1H NMR (500 MHZ, CDCl3) δ ppm 3.88 (2H, br s), 2.94 (1H, m), 2.86 (2H, m), 2.77 (1H, m), 1.83 (2H, d), 1.42 (2H, m), 1.38 (9H, s) and 1.20 (6H, d).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][NH2:10]>>[CH3:9][NH:10][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CN
Reactant: O=Cc1ccccn1
Product: CNCc1ccccn1

Procedure:
Scheme III illustrates the preparation of the preferred intermediate (14) useful for reaction with 3 to provide 2. 2-Picolinaldehyde (10) is reacted with methylamine, followed by hydrogenation, to provide 2-(N-methyl)aminomethylpyridine (11). Reaction of 11 with the methyl or benzyl ester of N-phenoxycarbonyl-L-valine (12) provides 13. Hydrolysis (R=Me) or hydrogenation (R=benzyl) of 13 provides 14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][N:15](C(OC=C)=O)[CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][CH2:26][CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:30]>C(O)C>[ClH:30].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][NH:15][CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][CH2:26][CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C(=O)CCC1)C2c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCO
Product: O=C1CCCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CNCC1=O)N2

Procedure:
A solution of the product from Example 2B (0.25 g) in ethyl alcohol (20 mL) was treated with 6M HCl (20 mL) and heated to reflux for 1.5 hours. The ethyl alcohol was evaporated and the aqueous portion basified with 1N sodium hydroxide. The basified solution was extracted with methylene chloride (3×). The combined methylene chloride extractions were concentrated and the residue was purified by flash chromatography over silica gel (10:90:1 ethanol/methylene chloride/saturated ammonium hydroxide) to provide the title compound (0.10 g) which was converted to the hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:9][C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1
Reactant: Oc1ccc(F)cc1
Reactant: OCc1ccncc1Br
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OCc2ccncc2Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a solution of (3-bromo-pyridin-4-yl)-methanol (650 mg, 3.5 mmol), 4-fluoro-phenol (260 mg, 2.3 mmol) and PPh3 (1.7 g, 6.4 mmol) in THF (50 mL) is added a solution of di-tert-butyl azodicarboxylate (1.2 g, 5 mmol) in THF at 0° C. After addition, the mixture is stirred at room temperature for 16 hrs. The solvent is removed and the residue is purified by flash column chromatography to give 600 mg of 3-bromo-4-(4-fluoro-phenoxymethyl)-pyridine.
Reaction SMILES: C[C:2]1(C)[CH2:7][O:6][P:5]([CH2:9][OH:10])(=[O:8])[O:4][CH2:3]1.[CH3:12]C1(C)COP(=O)OC1>>[OH:10][CH2:9][P:5]1(=[O:8])[O:6][CH:7]([CH3:12])[CH2:2][CH2:3][O:4]1
Reactant: CC1(C)CO[PH](=O)OC1
Reactant: CC1(C)COP(=O)(CO)OC1
Product: CC1CCOP(=O)(CO)O1

Procedure:
5,5-dimethyl-2-(hydroxymethyl)-2-oxo-1,3,2-dioxaphosphorinan from 5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][N:21]1[C:25]([NH2:26])=[CH:24][CH:23]=[N:22]1.CCOC(C)=O>C(O)(C)C>[CH3:20][N:21]1[C:25]([NH:26][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)=[CH:24][CH:23]=[N:22]1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: Cn1nccc1N
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cn1nccc1Nc1ncc2c(n1)CCN(C(=O)c1cccnc1)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 1-methyl-1H-pyrazol-5-amine (0.010 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 62.3% yield (0.019 g, 0.057 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N:4][NH:5][C:6]=1[CH2:7][CH2:8][CH2:9]Cl.[OH-].[K+]>C(O)(C)C.O>[Br:1][C:2]1[C:3]([CH3:11])=[N:4][N:5]2[CH2:9][CH2:8][CH2:7][C:6]=12
Reactant: Cc1n[nH]c(CCCCl)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1nn2c(c1Br)CCC2
Yield: 49 %

Procedure:
To a solution of 4-bromo-5-(3-chloro-propyl)-3-methyl-1H-pyrazole (2.42 g, 10.2 mmol) in isopropyl alcohol (35 mL) was added KOH (0.86 g, 15.3 mmol) dissolved in water (7 mL). The reaction was heated to reflux for 4 h. After cooling the reaction was partially concentrated, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated to give a light yellow oil as the desired product (1.01 g, 5.0 mmol). MS m/z 203.4 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=2[F:22])=[C:8]([CH3:23])[N:7]=1>C(Cl)Cl>[Cl:12][C:10]1[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:3])=[CH:16][C:15]=2[F:22])=[C:8]([CH3:23])[N:7]=[C:6]([NH2:5])[N:11]=1
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccc(CO)cc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(N)nc(Cl)c1Cc1ccc(CCl)cc1F
Temperature: 25 °C

Procedure:
Thionyl chloride (0.078 mL) was added to a stirred solution of the product from step (i) (0.30 g) in DCM (5 mL). The mixture was stirred at rt for Ih and then the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to give the subtitle compound, 0.13 g.