Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:41]=2[C:42](O)=[O:43])=[CH:34][CH:33]=1>CN(C)C=O.O>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]([F:50])([F:51])[F:52])=[CH:45][C:41]=2[C:42]([NH:11][C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)=[O:43])=[CH:34][CH:33]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (122 mg, 0.64 mmol), 3-pyridinamine (59.9 mg, 0.64 mmol), HOBT (63.4 mg, 0.41 mmol) and diisopropylethylamine (0.11 ml, 0.64 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 119; 100 mg, 0.32 mmol) in N,N-dimethylformamide (5 ml) and the mixture was stirred at room temperature overnight. The mixture was then heated to 70° C. for 5 hours. The mixture was diluted with water (25 ml) and extracted with ethyl acetate (3×25 ml). The organics were combined, evaporated under reduced pressure on a buchi and the residue was purified using an MDAP to yield the title compound. 85 mg.
Reaction SMILES: [CH:1]([C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[CH2:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([N:6]1[CH2:5][CH2:4][C:3]([CH:1]=[CH2:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC1(C(=O)OCC)CCNCC1
Solvent: ClCCl
Product: C=CC1(C(=O)OCC)CCN(S(C)(=O)=O)CC1
Yield: 98 %

Procedure:
Following the procedure reported in Example 84, the N-Boc group of 1-tert-butyl 4-ethyl 4-vinylpiperidine-1,4-dicarboxylate 84a (450 mg) was removed via treatment with 4N HCl in dioxane/DCM at RT for 1 h to give ethyl 4-vinylpiperidine-4-carboxylate. Ethyl 4-vinylpiperidine-4-carboxylate reacted with MsCl with TEA in DCM at RT for 18 h to give ethyl 1-(methylsulfonyl)-4-vinylpiperidine-4-carboxylate 85a (409 mg, 98% yield). LCMS [M+H]+=249.90 (-Boc); Tr=1.96 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([NH:23]C=O)=[N:17][C:18]=2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:26][CH2:27][CH3:28].[Na+]>C(O)C>[NH2:23][C:16]1[N:15]=[C:14]2[C:19]([N:20]=[CH:21][N:13]2[O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:18]([O:26][CH2:27][CH3:28])[N:17]=1
Reactant: O=CNc1nc(Cl)c2ncn(OCCCOCc3ccccc3)c2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N)nc2c1ncn2OCCCOCc1ccccc1
Yield: 8 %

Procedure:
A solution of 9-(3-benzyloxyprop-1-oxy)-6-chloro-2-formamidopurine (500 mg, 1.38 mmol) in 0.4M sodium ethoxide in ethanol (10 ml) was heated at 80° C. for 2.5 hours. The mixture was then cooled and evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the solution was brought to pH 7 with dilute hydrochloric acid. The aqueous solution was extracted with chloroform (2×20 ml) and the combined extracts were washed with water (10 ml), dried (magnesium sulphate) and evaporated under reduced pressure. Column chromatography on silica gel (eluted with chloroform-ethanol, 50:1) yielded the title compound (390 mg, 8%). IR: υmax (KBr) 3353, 3217, 1652, 1611, 1579, 1506, 1461, 1445, 1407 cm-1. 1H NMR: δH [(CD3)2SO] 1.35 (3H, t, J=7.2 Hz, CH3CH2O), 1.95 (2H, quintet, J=6.3, 6.6 Hz, CH2CH2CH2), 3.60 (2H, t, 6.3 Hz), 4.37 (2H, t, J=6.6 Hz, CH2ON), 4.42 (2H, quartet, J=7.2 Hz, CH3CH2O), 4.48 (2H, s, CH2Ph), 6.55 (2H, br.s, D2O exchangeable, NH2), 7.33 (5H, m, Ph), 8.07 (1H, s, H-8).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][N:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:18]([CH:19]3[CH2:24][O:23][CH2:22][CH2:21][O:20]3)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=2[N:14]=1)=[O:8].[F:30][C:31]([F:35])([F:34])[CH2:32][OH:33].C(Cl)(Cl)Cl>O1CCOCC1.CN(C=O)C>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:27]=[CH:28][N:29]=[C:4]([O:33][CH2:32][C:31]([F:35])([F:34])[F:30])[CH:5]=3)=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(OCC(F)(F)F)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide sodium hydride and 2,2,2-trifluoroethanol in dioxane and DMF. [α]D20=+11.3° (c=0.11, CHCl3), ES-MS m/e (%): 470 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:31](=[O:32])([O:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:23][CH:22]=1)[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(COC(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. mixture of 9.0 g of product from Example 19, 4.44 g of pyridine and 70 ml of methylene chloride is added, dropwise, 5.28 of phenyl chloroformate. The reaction is stirred at 0° C. for 15 minutes; followed by room temperature for 30 minutes. The mixture is poured into saturated sodium bicarbonate and the aqueous layer is extracted with methylene chloride. The combined organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 0-5% ethyl acetate/hexane) to give 12.6 g of colorless prisms.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH:4]3[OH:11])[CH2:2]1)[CH2:8]2.[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1>>[Cl:12][C:13]1[N:14]=[N:15][C:16]([O:11][CH:4]2[CH:5]3[CH2:10][N:1]4[CH2:8][CH:7]([CH2:9][CH:3]2[CH2:2]4)[CH2:6]3)=[CH:17][CH:18]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OC1C2CC3CC1CN(C3)C2
Product: Clc1ccc(OC2C3CC4CC2CN(C4)C3)nn1

Procedure:
Prepared from 1-azaadamantan-4-ol (3:2 diastereomer mixture; 150 mg, 0.979 mmol; see WO 9215579) and 3,6-dichloropyridazine (182 mg, 1.22 mmol; Aldrich) according to Method B to afford the title compound as a mixture of stereoisomers: MS (DCI/NH3) m/z=266 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18](OC)=[O:19].[CH3:22][CH:23]([SH:25])[CH3:24]>>[F:16][C:14]([F:15])([F:17])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[S:5][C:4]([CH2:18][OH:19])=[C:3]([CH2:2][S:25][CH:23]([CH3:24])[CH3:22])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Reactant: CC(C)S
Product: CC(C)SCc1cc(-c2ccc(C(F)(F)F)cc2)sc1CO

Procedure:
The title compound was prepared using methyl 3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate (intermediate 132) and isopropylthiol.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([NH:10][C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)[C:7]([C:20]([NH2:22])=[O:21])=[CH:6][N:5]=1)=O.[C:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])(=[O:25])[CH3:24].CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[C:23]([NH:26][C:27]1[CH:28]=[C:29]([NH:30][C:4]2[N:9]=[C:8]([NH:10][C:11]3([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:13][CH2:12]3)[C:7]([C:20]([NH2:22])=[O:21])=[CH:6][N:5]=2)[CH:31]=[CH:32][CH:33]=1)(=[O:25])[CH3:24]
Reactant: CS(=O)c1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NC3(c4ccccc4)CC3)n2)c1
Temperature: 100 °C
Yield: 59 %

Procedure:
To a solution of 2-(methylsulfinyl)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (50 mg, 0.16 mmol) in NMP (1 mL) was added 3-acetamidoaniline (27 mg, 0.18 mmol) and pTsOH*H2O (30 mg, 0.16 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (38 mg). MS found for C22H22N6O2 as (M+H)+ 403.5. λ=251.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([CH3:10])[C:7]=1[N:8]=[O:9].[OH:12]O>C(O)(=O)C.N.N.N.N.N.N.O.O.O.O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O>[CH3:10][C:6]1[CH:5]=[C:4]([OH:11])[CH:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:12])=[O:9]
Reactant: Cc1cc(O)cc(C)c1N=O
Reactant: OO
Agent: O=[Mo](=O)(O)O
Agent: O=[Mo](=O)=O
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 3,5-dimethyl-4-nitrosophenol (70.63 g) from above and (NH4)6Mo7O24.4H2O) (2.83g) in 770 ml of glacial acetic acid was warmed to 100° C. 30% H2O2 (84 ml) was added to the mixture in 10 ml portions until an exothermic reaction was observed. The reaction mixture was then stirred and the remainder of the H2O2 solution added in small portions. The reaction mixture was heated and stirred until a clear dark red solution results. A yellow-orange solid precipitated from the solution after stirring for another 20-30 minutes. The reaction mixture was stirred overnight and filtered to give a small amount of a yellow solid and a clear dark red filtrate. The red filtrate was concentrated in vacuo and partitioned between water and ether. The aqueous layer was washed with ether and the combined ether extracts washed with 10% sodium carbonate until the aqueous layer becomes basic. The ether extract was dried over anhydrous sodium sulfate, filtered, concentrated and allowed to cool overnight. After cooling in an ice bath the mixture was filtered to give 49.5 g of 3,5-dimethyl-4-nitrophenol as a yellow-green solid. Mp. 106-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1N.N([O-])=O.[Na+].[ClH:18]>O>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[Cl:18]
Reactant: Cl
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Temperature: -6 °C
Reaction time: 0.5 h

Procedure:
2,6-Dichloro-4-trifluoromethylaniline (3.3 kg) in concentrated hydrochloric acid (25 liters) was stirred for 1 hour and then cooled to -6° C. A solution of sodium nitrite (1.41 kg) in water (3 liters) was added over a period of 4 hours keeping the temperature between -5° and -12°. The mixture was then stirred between -5° and 0° until all solid had dissolved (3.5 hours). The mixture was then added in 2 liter portions over a period of 35 minutes to a solution of cuprous chloride (1.5 kg) in concentrated hydrochloric acid with stirring. The dark solution was left to stand for 30 minutes, filtered, and extracted with dichloromethane (1×15 liters, then 2×10 liters). The extracts were washed with water (2×25 liters) dried (MgSO4) and evaporated under reduced pressure to give 3,4,5-trichlorobenzotrifluoride (2.2 kg) with a boiling range of 98°- 100°/40 Torr.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:35])[CH:21]([O:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:53])[C@@H:15]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si](C(C)(C)C)(C)C)[CH2:39]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:35])[CH:21]([O:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:53])[C@@H:15]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([OH:45])[CH2:39]2)=[CH:10]1
Reactant: CCC(Oc1ccc2ccccc2c1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc2ccccc2c1)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 28.5 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.25 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-naphthyloxy)butyryloxy]-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 100, above] and 24.6 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.25 g of the title compound as white crystals, melting at between 124° and 127° C.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][NH2:11])C1C=CC=CC=1.[CH2:12]([N:14]1[C:26]2[CH:25]=[CH:24][C:23]([C:27]([OH:29])=O)=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13]>>[NH2:8][CH2:9][CH2:10][NH:11][C:27]([C:23]1[CH:24]=[CH:25][C:26]2[N:14]([CH2:12][CH3:13])[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:29]
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Reactant: NCCNCc1ccccc1
Product: CCn1c2ccccc2c2cc(C(=O)NCCN)ccc21
Yield: 92 %

Procedure:
N1-Benzyl-ethane-1,2-diamine (6.0 g, 25.1 mmol) was coupled with 9-Ethyl-9H-carbazole-3-carboxylic acid as described in example 81 to afford, after chromatographic purification (silica; 3% MeOH/CH2Cl2) 9-Ethyl-9H-carbazole-3-carboxylic acid (2-benzylamino-ethyl)-amide (4.5 g, 48%) (MS m/z @ 372 (m+1). This material was subjected to catalytic hydrogenation ((10%Pd—C/H2 @ 50 psi) in EtOH/AcOH to afford 9-Ethyl-9H-carbazole-3-carboxylic acid (2-amino-ethyl)-amide (3.16 g, 92%) as a white solid MS m/z @ 282 (m+1). This material was reductively aminated using sodium triacetoxyborohydride and thiazole-2-carbaldehyde similarly to conditions described for example 75 to afford the title compound (350 mg, 65%). MS m/z @ 379 (m+1).
Reaction SMILES: [C:1](=[O:21])([O:17][CH:18](Cl)[CH3:19])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]([O:13][N+:14]([O-:16])=[O:15])[CH2:8][O:9][N+:10]([O-:12])=[O:11].[CH2:22]([C:26]1[N:27]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:28]([C:32]([OH:34])=[O:33])=[C:29]([Cl:31])[N:30]=1)[CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:22]([C:26]1[N:27]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[NH:52][N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:28]([C:32]([O:34][CH:18]([O:17][C:1]([O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]([O:13][N+:14]([O-:16])=[O:15])[CH2:8][O:9][N+:10]([O-:12])=[O:11])=[O:21])[CH3:19])=[O:33])=[C:29]([Cl:31])[N:30]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Cl)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(5R)-5,6-bis(nitrooxy)hexyl 1-chloroethyl carbonate (7.67 g, 23.2 mmol) was added to a stirred solution of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (6.30 g, 9.3 mmol) and Cs2CO3 (3.02 g, 9.3 mmol) in DMF (186 mL). The solution was stirred at 70° C. for 2 h. Water (50 mL) was added and the solution was extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was redissolved in MeOH (186 mL). After stirring at 70° C. for 2 h, the solution was concentrated in vacuo. The residue was purified by HPLC chromatography (50×100 mm C-18) eluting with 40-100% MeCN/water+0.05% TFA. The diastereomers were then separated by HPLC chromatography on silica gel (ChiralPak AD-H) eluting with 20% MeOH in supercritical CO2 to give the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.06 (d, J=7.5 Hz, 1H), 7.62 (td, J=7.5, 1.0 Hz, 1H), 7.56 (td, J=6.5, 1.0 Hz, 1H), 7.44 (d, J=6.5 Hz, 1H), 7.17 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 6.87 (q, J=5.5 Hz, 1H), 5.54 (d, J=6.0 Hz, 2H), 5.24 (ddd, J=13.0, 6.2, 3.0 Hz, 1H), 4.73 (dq, J=12.5, 1.5 Hz, 1H), 4.46 (dd, J=13.0, 6.5 Hz, 1H), 4.14-4.04 (m, 1H), 2.76 (t, J=7.7 Hz, 2H), 1.76-1.59 (m, 6H), 1.61 (d, J=5.5 Hz, 3H) 1.55-1.40 (m, 2H), 1.38 (hex, J=7.5 Hz, 2H), 0.90 (t, J=7.5 Hz, 3H); LCMS (M+H) found 731.1.
Reaction SMILES: B([O-])([O-])[O-].[Na+].[Na+].[Na+].O.[OH-].[Na+].[CH2:11]([O:13][C:14]([C@:16]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C@@H:17]1[CH:19]=[CH2:20])=[O:15])[CH3:12]>CS(C)=O>[CH2:11]([O:13][C:14]([C@@:16]1([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:15])[CH3:12]
Reactant: C=C[C@H]1C[C@@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 48 °C
Reaction time: 2 h

Procedure:
A solution of 5 L of 0.2M sodium borate buffer (pH 9) at 45° C. in a 20 L jacked reactor stirred at 400 rpm was treated with 3 L of DI water and 4 L of Savinase 16 L, type EX (Novozymes North America Inc.). When the temperature of the mixture closed to 45° C., the pH was adjusted to 8.5 with 10N NaOH. A solution of (1R,2S)/(1S,2R)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (200 grams) in 2 L DMSO was added to the reactor over a period of 40 minutes via addition funnel. The reaction temperature was then adjusted to 48° C. After 2 hours, the pH was adjusted to pH 9.0 with 10N NaOH. At 18 hours, enantio-excess of the ester reached 72% and the pH was adjusted to 9.0 with 10N NaOH. At 24 hours the temperature was lowered to 35° C. At 42 hours the temperature was raised to 48° C. and the pH was adjusted to 9.0 with 10N NaOH. Heating was stopped at 48 hours and the reaction was slowly cooled down to room temperature (about 25° C.) and stirred overnight. At 66 hours, the pH of the reaction mixture was 8.6. The mixture was extracted with MTBE (2×4 L). The combined MTBE extracts were washed with 5% NaHCO3 (6×300 mL) and water (3×300 mL) and concentrated to give enantiomerically pure (1R,2S)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow crystals (101A g; purity: 95.9% (210 nm, containing no acid; 98.6% ee).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1.[Br:14]NC(=O)CCC(N)=O.C(O)(=O)C.O>C(Cl)Cl>[Br:14][C:8]1[C:7](=[O:9])[N:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]2=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: O=c1cc(CCl)nc2ccccn12
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=c1c(Br)c(CCl)nc2ccccn12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3.564 g, 1.0 equiv.), N-bromosuccinamide (1.0 equiv.) and acetic acid (48.2 mL) was stirred at rt for 4.5 h, at this point LCMS showed reaction was complete. The mixture was poured into water (200 mL) and the resulting precipitate was collected by filtration, washed with water (200 mL) and dried to give an orange solid. The solid was dissolved in DCM (100 mL), dried over Na2SO4, filtered and cond under reduced pressure to give desired 3-bromo-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as an orange solid which was carried forward without any further purification: 1HNMR (400 MHz, DMSO-d6): δ 8.94-8.97 (dd,1H), 8.03-8.08 (m,1H), 7.76-7.80 (dd, 1H), 7.43-7.48 (m,1H), 4.7 (s,2H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(Cl)(Cl)Cl.O1CCOCC1>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: COc1ccc(N)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 67.8 %

Procedure:
To tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10) (50 mg, 0.108 mmole) was added 4-methoxyaniline (16 mg, 0.129 mmole, 1.2 eq) followed by cesium carbonate (70 mg, 0.216 mmole, 2 eq) and Xantphos (6.2 mg, 0.0108 mmole, 10 mole %). Dioxane (1.2 mL) was added and the flask flushed twice with nitrogen. Pd2(dba)3 complex (5 mg, 0.0054 mmole, 5 mole %) was added and the flask was flushed again with nitrogen (×3) and heated at 80° C. for 2 hours. The reaction was cooled and diluted with ethyl acetate (10 mL). The solution was washed with water (3 mL) and with brine, dried and evaporated to leave a gum. This was applied in chloroform to a 1 mm, 20×20 cm silica prep plate which was eluted with 9:1 dichloromethane:ethyl acetate. The product band was recovered with acetone. Solution evaporated and residue azeotroped with ethanol to leave the title compound (37 mg, 68%). 1H-NMR (d6-DMSO, 500 MHz): δ 1.45 (s, 9H), 1.60 (s, 9H), 3.72 (s, 3H), 6.78 (d, J=0.63 Hz, 1H), 6.87 (d, J=9.14 Hz, 2H), 7.39 (t, J=0.95 Hz, 1H), 7.48 (d, J=9.14 Hz, 2H), 8.02 (d, J=0.63 Hz, 1H), 8.41 (d, J=0.95 Hz, 1H), 8.43 (d, J=0.63 Hz, 1H), 8.73 (br s, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([CH3:16])[C:10]([SH:15])=[CH:11][CH:12]=[CH:13][CH:14]=1>C1C=CC=CC=1>[C:9]1([CH3:16])[C:10]([S:15][Cl:1])=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccccc1S
Solvent: c1ccccc1
Product: Cc1ccccc1SCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
N-chlorosuccinimide (5.34 g., 40 mmoles) was slurried in 50 ml. of benzene and cooled in an ice-water bath. o-Toluenethiol (4.96 g., 40 mmoles) in 50 ml. of benzene was added dropwise over 15 minutes. The reaction was warmed to room temperature and stirred for approximately 16 hours. The reaction mixture was filtered and o-toluenesulfenyl chloride (5.53 g.) obtained as an oil by evaporation in vacuo.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=4)[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>[Zn]>[NH2:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][C:16](=[C:6]3[C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=4[CH:10]=[CH:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]3=4)[CH2:17][CH2:18]2)=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(CCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Agent: [Zn]
Product: Nc1ccc(CCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 97.3 %

Procedure:
3-[4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]-1-(4-nitrophenyl)propane (compound 7) was reduced by zinc. Yield 97.3%.