Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[C:24]([CH3:30])[N:23]=2)=[CH:16]3)=[CH:10][N:9]=1)[CH3:7])(=O)=O.[C:31]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1>[C:31]([N:35]1[CH2:40][CH2:39][N:38]([C@H:6]([C:8]2[N:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:14][N:15]4[CH:16]=[C:17]([C:22]5[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[C:24]([CH3:30])[N:23]=5)[N:18]=[C:19]4[C:20]=3[CH:21]=2)[CH3:7])[CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)OS(C)(=O)=O)ncc2OCC3)n(C(C)C)n1
Reactant: CC(C)(C)N1CCNCC1
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2cc([C@H](C)N4CCN(C(C)(C)C)CC4)ncc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 1-{4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,12-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate (240 mg) and 1-tert-butylpiperazine (281 mg, 1.97 mmol) in dioxane (5.00 mL) was stirred at 100° C. for 16 hrs under N2 atmosphere. After removal of the solvents, the residue was purified with reverse phase Combi-flash eluting with a 20-28% gradient of CH3CN in 0.3% NH4HCO3 to afford the desired product. The isolated solid was further separated by chiral SFC (AD-H column, EtOH (0.1% DEA) isocratic) to give the two enantiomers 303 and 305.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)[CH2:7][C:8]([OH:10])=O)=[O:5])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:29][CH2:28]1>>[O:10]=[C:8]([N:27]1[CH2:28][CH2:29][CH:30]([N:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:31][CH2:32]1)[CH2:7][C:6]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[CH:21]=1)([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccc2c(c1)CCCC2)C(=O)OCC
Product: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1ccc2c(c1)CCCC2)C(=O)OCC

Procedure:
Prepared analogously to Example 76c) from 3,3-bis-ethoxycarbonyl-4-(5,6,7,8-tetrahydro-naphthalen-2-yl)-butanoic acid and 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@:6]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:14])[CH2:8][CH2:7]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][C@@:6]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]([CH3:18])([CH3:16])[CH3:17])[CH3:14])[CH2:8][CH2:7]1
Reactant: C[C@H](N1CC[C@](CCN=[N+]=[N-])(c2ccc(F)cc2)OC1=O)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Yield: 70.9 %

Procedure:
To a solution of (S)-6-(2-azidoethyl)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (219 mg, 0.63 mmol) in THF (5 mL) and H2O (0.25 mL) was added PPh3 (198 mg, 0.76 mmol), and the mixture was refluxed for 2 h. The solution was concentrated, and the residue was purified by preparative TLC to afford (R)-6-(2-aminoethyl)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (144 mg, 71%). 1H NMR (CDCl3): 0.61-0.69 (s, 9H), 1.02-1.08 (d, 3H), 1.98-2.14 (m, 3H), 2.23-2.31 (m, 1H), 2.48-2.56 (m, 1H), 2.58-2.67 (m, 1H), 2.77-2.86 (m, 1H), 3.07-3.12 (m, 1H), 4.33-4.40 (m, 1H), 6.98-7.04 (m, 2H), 7.21-7.24 (m, 2H).
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]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][CH:13]=1)C>C1COCC1>[S:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12]([CH2:11][CH2:10][OH:9])=[CH:13]1
Reactant: CCOC(=O)Cc1csc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(-1-benzothiophene-3-yl)acetate (1.1 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the 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-(1-benzothiophene-3-yl)ethanol, was obtained as white oil pure enough and taken to the next step without purification. Yield: 850 mg (95%); 179 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[N+:12]([C:10]1[C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[CH3:11])([O-:14])=[O:13]
Reactant: Cc1ccc2nc(C)sc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc2ccc(C)c([N+](=O)[O-])c2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 256.1 %

Procedure:
To a solution of 2,6-dimethylbenzothiazol (350 mg, 2.15 mmol) in Conc. H2SO4 (4 mL) was added HNO3 (69%, 0.3 mmol) at 0° C. After stirred at 0° C. for 0.5 h, the mixture was poured over ice-water. The precipitate was collected and washed with 5% sodium bicarbonate and water, recrystallized from ethanol to give 7-nitro-2,6-dimethylbenzothiazol as yellow solid (160 mg). The product (150 mg) was hydrogenated over 5% Pd/C in ethanol-THF (10:2 mL) at atmosphere pressure to give 2,6-dimethyl-benzothiazol-7-ylamine as yellow solid (120 mg). TLC single spot at Rf 0.55 (10% EtOAc/DCM); 1H NMR (270 MHz, DMSO): δ 7.07 (2H, s, ArH), 5.23 (2H, s, NH2), 2.73 (3H, s, CH3), 2.20 (3H, s, CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([CH3:14])[C@H:11]([N:15]2[CH:19]=[C:18]([CH2:20][OH:21])[N:17]=[N:16]2)[C@H:10]([NH:22]C(=O)OC(C)(C)C)[CH2:9]1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[F:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:53]=1[C:59]1[N:64]=[C:63]([C:65](O)=[O:66])[CH:62]=[CH:61][C:60]=1[F:68].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C.CN(C=O)C.CCOC(C)=O.CCO.C(Cl)Cl>[NH2:22][C@H:10]1[C@@H:11]([N:15]2[CH:19]=[C:18]([CH2:20][OH:21])[N:17]=[N:16]2)[C@@H:12]([CH3:14])[CH2:13][N:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:1][C:65](=[O:66])[C:63]2[CH:62]=[CH:61][C:60]([F:68])=[C:59]([C:53]3[C:52]([F:51])=[CH:57][CH:56]=[CH:55][C:54]=3[F:58])[N:64]=2)[CH2:9]1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1cc(CO)nn1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1n1cc(CO)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a round-bottomed flask was added tert-butyl (3R,4S,5S)-1-(3-aminopyridin-4-yl)-4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.) and BSA (2.5 equiv.) in Acetonitrile/DMF (4/1, 0.05 M) to give a orange suspension. The mixture was stirred at room temperature for 1 hr at which time all of the solids had dissolved into solution. The mixture was taken to dryness. The crude in DMF (0.10 M) was added EDCI (2.4 equiv.), HOAT (2.4 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (2.4 equiv.). The mixture was stirred at rt for 16 hrs. The reaction was taken to dryness and dissolved in EtOAc and cooled to 0° C. to precipitate the urea byproduct. The mixture was filtered and the organics were washed with H2O, dried over MgSO4, filtered and concentrated. To a solution of the residue in EtOH (0.01 M) was added potassium carbonate (10.0 equiv.). The mixture was stirred at room temperature for 2 hrs. The reaction was diluted with DCM and quenched with NaHCO300. The organics were separated and the aqueous solution was extracted with DCM. The combined organics were dried over MgSO4, filtered, and concentrated. The crude alcohol was then dissolved in 25% TFA/DCM. The solution was stirred at room temp for 1 hr. The volatiles were removed on the rotovap. The crude product was taken up in DMSO, filtered, purified via prep-HPLC to yield N-(4-((3R,4S,5S)-3-amino-4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-5-methylpiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 69% yield. LC/MS (m/z)=539.3 (MH+), Rt=0.57 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][Na]>C1COCC1.O>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([O:28][CH3:27])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[Na]
Reactant: FC(F)(F)c1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(N(Cc2ccccc2)Cc2ccccc2)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a stirred solution of N,N-dibenzyl-6-chloro-5-(trifluoromethyl)pyridin-2-amine (100 mg, 0.27 mmol) in THF (5 mL) was added freshly produced CH3ONa (42 mg, 0.78 mmol) at room temperature. The mixture was heated to reflux for 10 h and then cooled to the room temperature, diluted with water (5 mL) and extracted with CH2Cl2 (6 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography using 2%-10% EtOAc in petroleum ether as eluant to obtain N,N-dibenzyl-6-methoxy-5-(trifluoromethyl)pyridin-2-amine (90 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.4 Hz, 1H), 7.35-7.22 (m, 10H), 6.02 (d, J=8.4 Hz, 1H), 4.79 (s, 4H), 3.90 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:3]=1.[CH:24](=O)[CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH3:26])[CH2:10][CH2:9]2)=[C:4]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:3]=1
Reactant: CCC=O
Reactant: Cc1ccc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2ccc(C)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a mixture of 1-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (55 mg, 0.175 mmol) produced in Example (70b), propionaldehyde (20 mg, 0.350 mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (75 mg, 0.350 mmol), followed by stirring for 1 hour and 15 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 56 mg of 1-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][CH:31]=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(C1C=CC(C2SC=C(CCl)N=2)=CC=1)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:24][CH:25]=3)[S:30][CH:31]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: CC(C)(C)c1ccc(-c2nc(CCO)cs2)cc1
Agent: CC(C)(C)c1ccc(-c2nc(CCl)cs2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C(C)(C)C)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[2-(4-tert-butyl-phenyl)-thiazol-4-yl]-ethanol (prepared from 2-(4-tert-butyl-phenyl)-4-chloromethyl-thiazole (example 4 a]) in analogy to the sequence described in examples 13 a] to 13 d]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-thiazol-4-yl]-ethoxy}-3-fluoro-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-thiazol-4-yl]-ethoxy}-3-fluoro-phenyl)-2-ethoxy-propionic acid as a light yellow solid.
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].Br[C:9]1[C:10]([C:16]#[N:17])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:15][C:12]1[N:11]=[C:10]([C:16]#[N:17])[C:9]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1
Reactant: Clc1ncccn1
Reactant: Cc1ccc(Br)c(C#N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ncccn2)c(C#N)n1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
Isopropylmagnesium chloride-LiCl (37.9 ml, 36.5 mmol) was added portion wise (in overall 10 min) to a solution of 3-bromo-6-methyl-2-pyridinecarbonitrile (4 g, 20.30 mmol) in THF (150 ml) cooled to −70° C. (internal temperature). The reaction was kept to that temperature for 15 min. Then it was allowed to gently warm up to −40° C. in overall 1 hour. Then, it was cooled to −78° C. and zinc chloride (3.32 g, 24.36 mmol) was added. The resulting mixture was allowed to warm up to room temperature in 1 hour. Pd(Ph3P)4 (2.346 g, 2.030 mmol), 2-chloropyrimidine (3 g, 26.2 mmol) were added and the mixture was refluxed (external temperature 100° C.) until complete consumption of starting chloropyrimidine (3 hours). The reaction mixture was cooled to room temperature and poured into water (200 ml) cooled to 10° C. It was then extracted with EtOAc (5×200 mls). The collected organic phases, containing large amount of colloid material and water, were washed with brine (200 ml). The water phase was filtered over a gouch, and the solid material was washed with further EtOAc 2×300 mls). The collected organic phases were dried overnight over Na2SO4, filtered and concentrated to give (7 g) the crude material which was purified (Biotage Sp1 over a 240 g Silica Anolgix column, with a 25 g pre-column) to give the title compound D18 as yellow solid (1.8 g). UPLC (Acid GEN_QC_SS): rt=0.58 minutes, peak observed: 197 (M+1). C11H8N4 requires 196.
Reaction SMILES: [CH2:1]([Si]1(Cl)N(C)[C@H](C)[C@@H](C2C=CC=CC=2)O1)/[CH:2]=[CH:3]\[CH3:4].[CH:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.CCOC(C)=O>C1(C)C=CC=CC=1>[CH3:4][C@@H:3]([CH:2]=[CH2:1])[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C/C=C\C[Si]1(Cl)O[C@H](c2ccccc2)[C@@H](C)N1C
Reactant: O=CCCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C[C@H](C)[C@@H](O)CCc1ccccc1
Temperature: -10 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
Enantioselective crotylation of dihydrocinnamaldehyde to give (3S,4S)-4-Methyl-1-phenyl-hex-5-en-3-ol: To a cooled (−10° C.) solution of (4R,5R)-2-((cis)-but-2-enyl)-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (0.431 g, 1.5 mmol) in toluene (2.5 mL) was added dihydrocinnamaldehyde (0.132 mL, 1.0 mmol). The reaction mixture was allowed to stir for 12 hours at −10° C. To this solution was added 1N HCl (4 mL) and EtOAc (4 mL) and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organics were dried over MgSO4, filtered, and concentrated. HPLC analysis of the residue at this stage revealed a syn:anti diastereoselectivity of 10:1, and an enantiomeric excess for the major syn product of 81%. The residue was purified by chromatography on silica gel to afford 0.116 g (61%) of (3S,4S)-4-Methyl-1-phenyl-hex-5-en-3-ol (81% ee).
Reaction SMILES: [CH:1]([NH:4]/[C:5](/SC)=[CH:6]/[C:7]#[N:8])([CH3:3])[CH3:2].O.[NH2:12][NH2:13]>CCO>[CH:1]([NH:4][C:5]1[CH:6]=[C:7]([NH2:8])[NH:13][N:12]=1)([CH3:3])[CH3:2]
Reactant: NN
Reactant: CS/C(=C\C#N)NC(C)C
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cc(N)[nH]n1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A mixture of (Z)-3-(isopropylamino)-3-(methylthio)acrylonitrile (0.413 g, 2.64 mmol) and hydrazine monohydrate (0.38 mL, 7.93 mmol) in EtOH (6 mL) was heated to reflux for 16 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography, eluting with ethyl acetate, DCM/MeOH (9:1) to give N3-isopropyl-1H-pyrazole-3,5-diamine (0.231 g, 62% over 2 steps) as an oil.
Reaction SMILES: C([Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[CH:21][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.C(O)=O.[NH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([S:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]([C:53]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[NH:55][N:54]=3)=[O:52])=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>>[OH:28][C@H:27]([CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:24][CH:23]=1)[CH2:29][NH:33][CH2:34][CH:35]1[CH2:36][CH2:37][N:38]([S:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]([C:53]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[NH:55][N:54]=3)=[O:52])=[CH:46][CH:45]=2)(=[O:42])=[O:43])[CH2:39][CH2:40]1
Reactant: NCC1CCN(S(=O)(=O)c2ccc(NC(=O)c3n[nH]c4ccccc34)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: O=C(Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3ccc(O)cc3)CC2)cc1)c1n[nH]c2ccccc12
Yield: 13.4 %

Procedure:
Prepared from t-butyl-[4-(2S)-oxiranylmethoxy-phenoxy]-diphenylsilane (0.623 g, 1.54 mmol), (1H)-Indazole-3-carboxylic acid [4-(4-aminomethyl-1-piperidinyl-sulfonyl)-phenyl]-amide formate salt (0.71 g, xx mmol) and diisopropylethyl amine (0.41 mL) according to the procedure used for example 37 to give 0.12 g of the title compound as a white solid.
Reaction SMILES: CC(CCC[CH2:7][CH2:8][O:9][C:10]([C:12]1[C:17]([C:18]([O:20][CH2:21][CH2:22]CCCC(C)C)=[O:19])=CC=CC=1)=[O:11])C.C1(P(CC2C(CP(C3C=CC=CC=3)C3C=CC=CC=3)[O:46][C:45]3([CH2:65][CH2:64][CH2:63][CH2:62]3)[O:44]2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:44]1[C:45]2([CH2:65][CH2:64][CH2:63][CH2:62]2)[O:46][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]1[C:10]([O:9][CH2:8][CH3:7])=[O:11]
Reactant: c1ccc(P(CC2OC3(CCCC3)OC2CP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)CCCCCOC(=O)c1ccccc1C(=O)OCCCCCC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O=C1CCCC1
Product: CCOC(=O)C1OC2(CCCC2)OC1C(=O)OCC

Procedure:
Example 4 was repeated in which the DTDR was replaced by an equivalent amount of DODDR and the DIOP was replaced by an equivalent amount of (-)-2,3-bis(diphenylphosphinomethyl)-1,4-dioxaspiro[4,4]nonane, prepared by: (a) reacting L-(+)-diethyl tartrate with cyclopentanone in benzene in the presence of p-toluenesulphonic acid to give diethyl 1,4-dioxaspiro[4,4]nonan-2,3-dicarboxylate, b.p. 154°-158° C./6.0 mm., (b) reducing this with lithium aluminium hydride to give (-)-2,3-O-cyclopentylidene-L-threitol, b.p. 124°-130° C./0.2 mm., (c) converting this to (-)-1,4-ditosyl-2,3-O-cyclopentylidene-L-threitol m.p. 109°-115.5° C. by reaction with p-toluenesulphonyl chloride in pyridine and (d) treating with potassium and diphenylphosphine in tetrahydrofuran to give the desired compound m.p. 93°-95° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][C:19]=3[S:18]2(=[O:29])=[O:28])[CH2:9][CH2:8]1.[CH:30]([O:33]C(C)C)(C)[CH3:31]>C(OC(=O)C)(=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH:27][C:30](=[O:33])[CH3:31])=[CH:26][C:19]=3[S:18]2(=[O:28])=[O:29])[CH2:9][CH2:8]1
Reactant: CC(C)OC(C)C
Reactant: Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 ml of acetic anhydride are addedt o 0.06 mol of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-6-amino-1,2-benzoisothiazol-3(2H)one 1,1-dioxide, and the mixture is stirred at room temperature for 12 hours. It is then evaporatd to dryness, isopropyl ether is added and the mixture is stirred for 1 hour. It is then filtered and the colourless crystals are dried in vacuo.
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:26])[NH:9][CH:10]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:11]1)=[O:5].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[C:20]1([CH:17]2[CH2:16][CH2:15][CH:14]([N:12]3[CH2:11][CH:10]([NH:9][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]4[CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:2]=4[N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[O:26])[CH2:13]3)[CH2:19][CH2:18]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1CCNC1
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1F)NC1CN(C2CCC(c3ccccc3)CC2)C1
Product: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1N1CCCC1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from coupling of 2-fluoro-N-{[1-(4-phenyl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide (as prepared in Example 66) and pyrrolidine (Aldrich) using the procedure described in Example 69.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([N+:11]([O-])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].[Cl-].[NH4+]>[Fe].C(OCC)(=O)C>[F:8][C:7]1[C:2]([F:1])=[C:3]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:4]([NH2:11])=[C:5]([O:9][CH3:10])[CH:6]=1
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Yield: 89 %

Procedure:
To a stirred solution of (2,3-difluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (0.57 gm, 1.34 mmol) ethanol (20 ml), ammonium chloride (1.18 gm, 20.16 mmol) and iron powder (1.15 gm, 21.44 mmol) were added. This reaction mixture was kept stirring at reflux for 16 hours. The reaction mixture was allowed to cool and was filtered over celite and concentrated to dryness. The residue obtained was taken into ethyl acetate and was washed with water. The organic layer was dried over sodium sulfate and further purified by crystallization from ethanol to provide an off-white solid (0.47 gm, yield: 90.3%).