Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:16][CH:13]1[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Reactant: COc1cccc(C(=O)O)c1Cl
Product: COc1cccc(C(=O)NCC(CC2CC2)c2ccc(C(F)(F)F)nc2)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=413.1, tR (minutes, Method G)=2.84. [α]D20=+20.9 (c=0.86 mg/mL,CHCl3)
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=O)[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[CH2:8][N:5]2[CH2:6][CH2:7][C:2]([F:30])([F:1])[CH2:3][CH2:4]2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(CN2CCC(F)(F)CC2)n3-c2ccc(Cl)cc2)CC1
Yield: 57 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 4-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (57%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C:17]([CH2:18][CH2:19][C@:5]2([CH3:6])[C:4](=[O:21])[CH2:3]1)=[C:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:22]([O:1][C@@H:2]1[C@H:7]2[C@H:8]3[C:17]([CH2:18][CH2:19][C@:5]2([CH3:6])[C:4](=[O:21])[CH2:3]1)=[C:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1[C@@H](O)CC2=O
Solvent: c1ccncc1
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 20 g of 15α-hydroxyestra-4,9-diene-3,17-dione in 120 ml of pyridine is combined dropwise with 13.6 ml of benzoyl chloride and the mixture is stirred for one hour at room temperature. Subsequently the mixture is poured into ice water, extracted with dichloromethane, washed with sodium bicarbonate solution and water and concentrated under vacuum. The cooled crude product is chromatographed on silica gel, yielding 26.2 g of 15α-benzoyloxyestra-4,9-diene-3,17-dione.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:34][CH2:35][CH2:36][N:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[C:25]([O:28][CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16].CS(O[CH2:48][C@@H:49]1[O:53][C:52](=[O:54])[CH2:51][CH2:50]1)(=O)=O>C(#N)C>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:34][CH2:35][CH2:36][N:37]4[CH2:38][CH2:39][N:40]([CH2:48][C@@H:49]5[O:53][C:52](=[O:54])[CH2:51][CH2:50]5)[CH2:41][CH2:42]4)=[C:25]([O:28][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: Fc1ccc(Nc2ncnc3cc(OCCN4CCNCC4)c(OC4CCCC4)cc23)cc1Cl
Reactant: CS(=O)(=O)OC[C@H]1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC[C@H](CN2CCN(CCOc3cc4ncnc(Nc5ccc(F)c(Cl)c5)c4cc3OC3CCCC3)CC2)O1

Procedure:
160 mg of potassium carbonate and 50 mg of sodium iodide are added to 300 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-(piperazin-1-yl)-ethoxy]-quinazoline in 20 ml of acetonitrile. Then 170 mg of (R)-5-[(methanesulphonyl-oxy)methyl]-2-oxo-tetrahydrofuran are added. The reaction mixture is refluxed for four hours, then a further 0.10 g of (R)-5-[(methanesulphonyloxy)methyl]-2-oxo-tetrahydrofuran are added. After another ten hours of refluxing a further 0.12 g of (R)-5-[(methanesulphonyloxy)methyl]-2-oxo-tetrahydrofuran as well as 0.20 g of potassium carbonate and 70 mg of sodium iodide are added. The reaction mixture is refluxed for another five hours and then left to stand over a weekend. For working up the reaction mixture is filtered and the filtrate is concentrated by evaporation. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol/concentrated aqueous ammonia solution (95:5:0.05, later 93:7:0.1) as eluant. The title compound is obtained as a white solid.
Reaction SMILES: Cl.C(OC(=O)NC1(C(=O)NC2(C(=N)N)CC2)CC1)(C)(C)C.[C:22]([O:26][C:27](=[O:34])[NH:28][C:29]1([C:32]#[N:33])[CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23].C(OC(=O)NC1(C(=O)NC2(C(=N)N)CC2)CC1)(C)(C)C.[Br:55][C:56](=[CH:59][N:60](C)C)[CH:57]=O>CCO.CO>[C:22]([O:26][C:27](=[O:34])[NH:28][C:29]1([C:32]2[N:60]=[CH:59][C:56]([Br:55])=[CH:57][N:33]=2)[CH2:31][CH2:30]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1(C#N)CC1
Reactant: CN(C)C=C(Br)C=O
Agent: CC(C)(C)OC(=O)NC1(C(=O)NC2(C(=N)N)CC2)CC1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ncc(Br)cn2)CC1
Temperature: 80 °C

Procedure:
[1-(1-Carbamimidoyl-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester hydrochloride (1.0 g, 4.2 mmol) (made from (1-cyano-cyclopropyl)-carbamic acid tert-butyl ester using a procedure similar to that of [1-(1-carbamimidoyl-cyclopropyl-carbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester) and 2-bromo-3-dimethylamino-acrolein (1.1 g, 6.36 mmol) were combined in EtOH (2 mL) in a sealed tube. The reaction was capped and the mixture heated at 80° C. for 24 hours. The resulting black mixture was allowed to cool to room temperature. Methanol (20 mL) was then added to the reaction solution. The solids were filtered and the resulting solution was dried under reduced pressure. The residue was diluted with 50 mL CH2Cl2 and the solids were removed. The solution was concentrated and purified by normal phase flash chromatography on silica gel (0→50% EtOAc in hexanes) to give 800 mg of [1-(5-bromo-pyrimidin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(OCC)(=O)C>C1COCC1>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=2)[N:3]=[CH:4][N:5]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ncnc1Nc1ccc(OC(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a solution of 4,6-Dichloro-pyrimidine-5-carbaldehyde (3.06 g, 17.5 mmol) in THF (15 mL) was added 4-trifluoromethoxyaniline (3.09 g, 17.45 mmol) at 0° C. The mixture was stirred for 2 h and ethyl acetate (100 mL) was added. The organic layer was separated from brine, dried (Na2SO4) and concentrated to yield crude title compound as yellow solids. The compound was then purified by silica gel column chromatography to give the title compound as yellow crystals. (2.9 g, 55%). MS m/z 318.2 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][CH:42]([C@@H:66]1[CH2:70][C@H:69]([SH:71])[CH2:68][N:67]1[C:72]([O:74][CH2:75][C:76]1[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=1)=[O:73])[CH2:43][C:44]([N:46]1[CH2:50][CH2:49][C@H:48]([CH2:51][NH:52][C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])[CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:71][C@@H:69]3[CH2:68][N:67]([C:72]([O:74][CH2:75][C:76]4[CH:77]=[CH:78][C:79]([N+:82]([O-:84])=[O:83])=[CH:80][CH:81]=4)=[O:73])[C@H:66]([CH:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:50][CH2:49][C@H:48]([CH2:51][NH:52][C:53]([O:55][CH2:56][C:57]5[CH:58]=[CH:59][C:60]([N+:63]([O-:65])=[O:64])=[CH:61][CH:62]=5)=[O:54])[CH2:47]4)=[O:45])[CH2:70]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(NC[C@H]1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(O)CC(=O)N4CC[C@H](CNC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 75.9 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (199.5 mg) and (2S,4S)-2-[1-hydroxy-2-[(3R)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (202.3 mg), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[1-hydroxy-2-[(3R)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (237.1 mg) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH2:30]([NH:33][CH3:34])[CH:31]=[CH2:32]>CN(C)C(=O)C>[CH2:30]([N:33]([CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)[CH:31]=[CH2:32]
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C=CCNC
Solvent: CC(=O)N(C)C
Product: C=CCN(C)CCCCOC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with N-allyl-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-{4-[4-(allyl-methyl-amino)-butoxymethyl]-cyclohexylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as yellow solid, MS: 491 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:12]N1C(=O)CCC1=O>C(#N)C>[Cl:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1ccc2[nH]ncc2c1
Solvent: CC#N
Product: O=Cc1ccc2[nH]nc(Cl)c2c1
Temperature: 67.5 °C
Reaction time: 50 h
Yield: 54.4 %

Procedure:
To a solution of 1H-Indazole-5-carbaldehyde (3.2 g, 21.89 mmol) in acetonitrile (140 mL) was added N-Chlorosuccinimide (3.5 g, 26.27 mmol). After stirring for 50 hours at 65 to 70° C., the precipitate was filtered, washed with cold acetonitrile, abundantly with water and dried to afford the title compound as a white solid (2.15 g, 54%).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[S:13])=[C:10]([CH3:17])[C:9]=1[O:18][CH3:19]>ClCCl>[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:4])=[S:13])=[C:10]([CH3:17])[C:9]=1[O:18][CH3:19]
Reactant: COc1c(F)ccc(C(O)=S)c1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1c(F)ccc(C(=S)Cl)c1C
Yield: 103.5 %

Procedure:
2,4-Difluoro-3-methoxybenzoic acid (38.2 g) was added to a stirred solution of methyl mercaptan (9.7 g) in dry tetrahydroftran under an inert atmosphere. A solution of n-butyl lithium (162 ml of a 2.5M solution in hexane) was added dropwise at −78° C. After 1 hour the mixture was allowed to warm to 20° C. overnight and evaporated. Hydrochloric acid (2M) and ether were added and the organic phase washed (water), dried mil (magnesium sulphate) and evaporated. The residue was triturated with hexane to give 4-fluoro-3-methoxy-2-methylthiobenzoic acid (29.2 g), NMR 2.6 (s, 3H), 4.0 (s, 3H), 7.1 (m, 1H), 7.9 (m, 1H). oxalyl chloride (51.5 g) was added to a stirred solution of 4-fluoro-3-methoxy-2-methylthiobenzoic acid (29.2 g) in dichloromethane. After 3.5 hours the mixture was evaporated to give the title compound (33.0 g), used directly in the above reactions.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15](OS(C)(=O)=O)[CH2:14][C@H:13]2[C:22](=[S:24])[OH:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]3[CH2:14][C@H:13]2[C:22](=[O:23])[S:24]3)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(O)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1S[C@H]2C[C@@H]1N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2

Procedure:
To a solution of crude (2S,4R)-1-p-nitrobenzyloxycarbonyl -4-methanesulfonyloxy-2-pyrrolidinethiocarboxylic acid (4.0 g) obtained in Example 8 in methylene chloride (40 ml) was added pyridine (1.91 g). The mixture was heated under refluxing for 7 hours. After the reaction was over, the mixture was washed with aqueous 1 mole/1 hydrochloric acid solution. The organic layer was dried over magnesium sulfate. After the solvent was distilled, residue was purified by silica gel chromatography to give (1S,4S)-5-p-nitrobenzyloxycarbonyl-2-thia-5-azabicyclo-[2.2.1]heptan-3-one.
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[C-:30]#[N:31].[K+]>C1C=CC=CC=1.CCCCC[N+](CCCCC)(CCCCC)CCCCC.[Br-].O>[C:30]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: [C-]#N
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCC[N+](CCCCC)(CCCCC)CCCCC
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
In 2 ml of benzene are dissolved 0.5 mmol of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 0.1 mmol of tetra-n-amylammonium bromide, and a solution of 0.55 mmol of potassium cyanide in 0.55 ml of water is added at 15° C. The mixture is stirred vigorously for 15 minutes and treated in the same manner as Example 20 to give (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone with the (3R,4R):(3S,4S) ratio of 1:4.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:43]([NH:50][C:29]([C:26]1[C:24]2=[N:25][C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[C:21]([N:35]3[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]3)[C:22]([Cl:34])=[C:23]2[O:28][N:27]=1)=[O:31])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reactant: NCc1ccccc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)NCc4ccccc4)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and benzylamine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[NH4+]>O1CCCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[Cl:11][CH2:12][CH2:13][C:14]([C:2]1[O:1][CH:5]=[CH:4][N:3]=1)=[O:15]
Reactant: O=C(Cl)CCCl
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CCCl)c1ncco1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 228.6 %

Procedure:
To a solution of oxazole (2.93 g, 42.5 mmol) in tetrahydrofuran (150 ml) at −70° C. under a nitrogen atmosphere was added n-butyllithium (17 ml of a 2.5M solution in hexanes) dropwise and the solution stirred for 20 minutes. Zinc chloride (84.9 ml of a 1M solution in diethyl ether) was added and the solution warmed to 0° C. over 45 minutes. Solid cuprous iodide (8.09 g, 42.5 mmol) was added and after 10 minutes, 3-chloropropionyl chloride (8.38 ml, 87.8 mmol) was added. After 1 h, ethyl acetate and aqueous ammonium chloride solution were added. The organic layer was separated and washed sequentially with aqueous ammonium chloride solution, water and brine. The solution was dried (sodium sulphate) and evaporated to yield 15.5 g of the crude product as a red oil. This mixture was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=[O:20])[CH:17]=2)[N:12]=[C:11]([N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[S:24][CH2:23][CH2:22]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][OH:20])[CH:17]=2)[N:12]=[C:11]([N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[S:24][CH2:23][CH2:22]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OCc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of 4-(benzyloxy)-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carbaldehyde (3.0 g, 7.0 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) was added sodium borohydride (270 mg, 7.13 mmol) at 0° C. After being stirred at 0° C. for 15 minutes, the resulting mixture was warmed to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with a saturated aqueous solution of ammonium chloride (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 2.85 g of the desired product as a yellow solid (yield was 95%), MS obsd. (ESI+) [(M+H)+] 430.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH2:4]1.C1C(=O)N([Br:23])C(=O)C1>C(#N)C>[Br:23][C:11]1[C:12]([NH2:15])=[N:13][CH:14]=[C:9]([C@@H:5]2[CH2:6][CH2:7][CH2:8][C@H:3]([O:2][CH3:1])[CH2:4]2)[N:10]=1
Reactant: CO[C@H]1CCC[C@@H](c2cnc(N)cn2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CO[C@H]1CCC[C@@H](c2cnc(N)c(Br)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
(+/−)-N,N-di-Boc-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine (184 mg, 0.452 mmol) in DCM (4. 515 mL) was added HCl (4M in dioxane) (4.515 mL, 18.06 mmol). The reaction mixture was stirred at room temperature overnight. After the volatile material was removed in vacuo, the residue was dissolved in EtOAc. The organic layer was washed by NaHCO3 solution, water and brine, dried over anhydrous Na2SO4, and concentrated affording (+/−)-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine in quantitative yield. LCMS (m/z): 208 (MH+), 0.43 min. To a solution of (+/−)-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine (54 mg, 0.261 mmol) in acetonitrile (4. 008 μL) was added NBS (48.7 mg, 0.274 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. After quenched with NaHCO3, extracted with EtOAc three times. The organic layer was washed by water and brine, dried over anhydrous Na2SO4, and concentrated to afford 75 mg of (+/−)-3-bromo-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine in quantitative yield. LCMS (m/z): 286 (MH+), 0.73 min.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[CH:54][CH:53]=[C:52]3[C:48]=2[CH:49]=[CH:50][NH:51]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.Cl.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2.C(Cl)Cl>[NH:51]1[C:52]2[C:48](=[C:47]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[C:4]([C:20]4[O:21][C:22]([CH2:25][N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:23][N:24]=4)[CH:3]=3)[CH:55]=[CH:54][CH:53]=2)[CH:49]=[CH:50]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: c1cc(-c2cc(-c3ncc(CN4CCNCC4)o3)c3cn[nH]c3c2)c2cc[nH]c2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
1,1-Dimethylethyl 4-({2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methyl)-1-piperazinecarboxylate (303 mg, 0.543 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (172 mg, 0.706 mmol, available from Frontier Scientific), chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (30 mg, 0.054 mmol, available from Fluka) and tripotassium phosphate (346 mg, 1.629 mmol) were dissolved in 1,4-Dioxane (10 mL) and Water (2.5 mL). The reaction vessel was sealed and heated in Biotage Initiator microwave at 150° C. for 30 min. Aqueous 2M NaOH (5 ml) was then added and the mixture stirred for 2 hours. An additional portion of aqueous 2M NaOH (3 ml) was added and stirring continued until deprotection appeared complete by LCMS analysis. DCM was then added and the mixture was passed through a phase separator. The organic phase was collected. The aqueous phase was back extracted with DCM then the organic phases were combined and evaporated to give a brown oil. This was dissolved in 5 ml of 4M HCl in 1,4 dioxane and left stirring. The mixture was concentrated in vacuo and the resultant solid partitioned between DCM and 2M aqueous HCl. The aqueous phase was basified with 2M aqueous NaOH, then washed with DCM. The organic phase was concentrated in vacuo, then the residue dissolved in 2 ml DMSO/MeOH (1:1) and purified by MDAP (Method H). Combining appropriate fractions and concentrating by blow down under nitrogen at 40° C., afforded the title compound (43 mg).