Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([O:25][CH3:26])(=[O:24])[C:22]#[CH:23]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:23][C:22]([C:21]([O:25][CH3:26])=[O:24])=[C:6]2[N:7]1[CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=12
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccsc1-2
Reactant: C#CC(=O)OC
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2

Procedure:
ba) A suspension of 31.65 g of 5,6-dihydro -3-hydroxy-2-phenylthiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) in 770 ml of toluene was treated with 10.94 g of methyl propiolate, the mixture was heated under reflux until the reaction has finished, the reaction mixture was evaporated in vacuo and the residue was chromatographed on silica gel with toluene/ethyl acetate (9:1). There was obtained methyl 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate as yellow crystals of m.p. 116° (from ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:12]=1.C[OH:27]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]([NH2:23])=[O:27])=[CH:20][CH:19]=2)[N:12]=1
Reactant: Cc1cc(C)c(Nc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Reactant: CO
Solvent: O
Product: Cc1cc(C)c(Nc2ccnc(Nc3ccc(C(N)=O)cc3)n2)c(C)c1
Yield: 56 %

Procedure:
A mixture of 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (0.00303 mol) and NaBO3.4H2O (0.00911 mol) in CH3OH (30 ml) and H2O (10 ml) was stirred and refluxed for 4 days. The reaction mixture was cooled. The precipitate was filtered off and the precipitate (!) was purified by flash column chromatography over silica gel (eluent: CH2Cl2/CH3OH gradient from 100/0 to 95/5). The desired fractions were collected and the solvent was evaporated, yielding 0.586 g (56%) of 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide (comp. 40). The filtrate (!) was purified by reversed-phase HPLC (eluent gradient: ((0.5% ammoniumacetate in H2O)/CH3CN 90/10)/CH3OH/CH3CN (0 minutes) 75/25/0, (44 minutes) 0/50/50, (57 minutes) 0/0/100, (61.1-70 minutes) 75/25/0). Three desired fraction groups were collected and their solvent was evaporated, yielding 0.18 g of 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide, N3-oxide (comp. 49) and 0.030 g of 4-[[4-(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]-amino]benzamide, N1-oxide.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: Cc1cc(Oc2ccccc2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(Oc2ccccc2)cc(C)c1-c1csc(N)n1
Yield: 59.1 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-phenoxyphenyl)ethanone (5.18 g, 16.2 mmol) and thiourea (1.24 g, 16.3 mmol) in 95% EtOH (23.2 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-phenoxyphenyl)thiazol-2-amine (2.84 g) as yellow solids in 59% yield: 1H NMR (500 MHz, CDCl3) δ 7.33 (t, J=7.5 Hz, 2H), 7.26 (t, J=7.5 Hz, 1H), 7.10 (d, J=7.3, 2H), 6.72 (s, 2H), 6.30 (s, 1H), 5.18 (bs, 2H), 2.14 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:39]=[CH:38][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:15]=3)[C:10]([CH:24]=[N:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:9]2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>C1COCC1>[F:40][C:2]([F:1])([F:41])[C:3]1[CH:39]=[CH:38][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[C:10]([CH:24]=[N:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:9]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)COc1ccc2c(c1)c(C=NOCc1ccc(C(F)(F)F)cc1)cn2Cc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc2c(c1)c(C=NOCc1ccc(C(F)(F)F)cc1)cn2Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a solution of the product of step 4 (350 mg, 0.605 mmoles) in THF (2 mL) Water: (2 ml), lithum hydroxide monohydrate (38 mg, 0.908 mmoles), was added and the reaction mixture was stirred at 25° C. for 3 hours. The reaction mixture was poured into ice cold water, acidified by dil.HCl and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure to yield 250 mg (77%) of product as solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2.[CH3:16][C:17]1[C:21]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[C:20]([CH3:31])[NH:19][C:18]=1[CH:32]=O>>[CH3:16][C:17]1[C:21]([C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)=[O:23])=[C:20]([CH3:31])[NH:19][C:18]=1[CH:32]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[NH:10][C:9]1=[O:15]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2nccs2)N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4nccs4)c32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
4-Thiazol-2-yl-1,3dihydro-indol-2-one (54 mg, 0.25 mmol) was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (69 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[O:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]3)[CH2:11][O:10]2)=[CH:4][C:3]=1[F:24].[CH3:25][N:26]1C(=O)CCC1>>[C:25]([C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[O:14][CH2:13][C@H:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]3)[CH2:11][O:10]2)=[CH:4][C:3]=1[F:24])#[N:26]
Reactant: CN1CCCC1=O
Reactant: CCCC1CCC(C2COC(c3cc(F)c(Br)c(F)c3)OC2)CC1
Product: CCC[C@H]1CC[C@H]([C@H]2CO[C@H](c3cc(F)c(C#N)c(F)c3)OC2)CC1
Temperature: 25 °C

Procedure:
7.3 g (0.018 mol) of 2-(4'-bromo-3',5'-difluorophenyl)-5-(4'-propylcyclohexyl)-1,3-dioxane, 2.5 g (0.027 mol) of CuCN2 and 54 cm3 of NMP were refluxed for 2 hours with a mantle heater. After cooling the reactant to room temperature, 40 cm3 of EDA was added, it was poured into 50 cm3 of ice water, extracted with chloroform and washed with an aqueous EDA solution and water. The chloroform was removed, and the residue was dissolved in hexane and washed with water to remove the NMP. The hexane was removed, and the residue was treated in a silica gel column with chloroform as the solvent. The chloroform was removed, and the residue was repeatedly recrystallized in a solvent mixture of acetone and methanol until there were no cis forms to obtain 1.4 g (0.004 mol) of trans-2-(4'-cyano-3',5'-difluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. The phase transition temperature of this compound was measured with DSC as follows. ##STR17## (here, C shows crystals, N shows the nematic phase and I shows isotropic liquid.)
Reaction SMILES: [CH3:1][C@@H:2]([N:9]=[C:10]=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O:13][C:14](=[O:64])[C@@H:15]([NH:31][C:32]([C@@H:34]1[CH2:43][C:42]2[CH:41]=[C:40]3[O:44][CH2:45][C@H:46]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH2:55][C:56]5[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=5)[CH:49]=4)[O:47][C:39]3=[CH:38][C:37]=2[CH2:36][NH:35]1)=[O:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[C:24]=2[CH3:30])=[CH:19][CH:18]=1.CO>C(Cl)Cl>[Cl:63][C:58]1[CH:57]=[C:56]([CH:61]=[CH:60][C:59]=1[Cl:62])[CH2:55][O:54][C:50]1[CH:49]=[C:48]([C@H:46]2[CH2:45][O:44][C:40]3=[CH:41][C:42]4[CH2:43][C@@H:34]([C:32]([NH:31][C@@H:15]([CH2:16][C:17]5[CH:22]=[CH:21][C:20]([C:23]6[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[C:24]=6[CH3:30])=[CH:19][CH:18]=5)[C:14]([OH:64])=[O:13])=[O:33])[N:35]([C:10](=[O:11])[NH:9][C@@H:2]([C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)[CH3:1])[CH2:36][C:37]=4[CH:38]=[C:39]3[O:47]2)[CH:53]=[CH:52][CH:51]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Reactant: C[C@@H](N=C=O)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N[C@H](C)c3ccccc3)O[C@@H](c3cccc(OCc4ccc(Cl)c(Cl)c4)c3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
(R)-(+)-α-Methylbenzyl isocyanate (5 mg) was added to a solution of (S)-2-({(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (20 mg) in 0.5 mL DCM and stirred for 1 h at room temperature. The reaction mixture was directly loaded onto a silica gel column (1:1 EtOAc/hexanes to 6% MeOH in 1:1 EtOAc/hexanes) to isolate the desired product (16 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([NH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2nc(N)n3nc(-c4ccco4)nc3n2)cc1
Product: COc1ccc(-c2nc(NC(C)=O)n3nc(-c4ccco4)nc3n2)cc1

Procedure:
A solution of 7-amino-2-(2-furyl)-5-[4-methoxyphenyl][1,2,4]triazolo[1,5-a][1,3,5]triazine (0.23 g) in acetic anhydride (10 ml) was heated on the steam-bath for 18 hours. The solvent was then evaporated in vacuo and the residue was purified by chromatography on silica-gel eluting with dichloromethane containing ethyl acetate (5% v/v). The solid obtained from the chromatography was crystallised from ethanol and gave 7-acetylamino-2-(2-furyl)-5-[4-methoxyphenyl][1,2,4]triazolo[1,5-a][1,3,5]triazine m.p. 243°-6° C.; microanalysis, found: C, 58.0; H, 4.0; N, 23.9% C17H14N6O3 requires C, 58.3; H, 4.0; N, 24.0%; NMR 2.50 (s, NHCOCH3), 3.87 (s, 3H, CH3O), 6.75 (d of d, 1H, furyl-4H), 7.12 and 8.42 (A2B2 pattern, 4H, phenyl-H), 7.32 (d, 1H, furyl-3H), 7.98 (d, 1H, furyl-5H) and 11.42 (s, H, NHCOCH); m/e 351 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8](Br)[CH2:9][CH2:10]Cl)=[O:7])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[I-].[K+]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:9][CH2:10][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(c1ccc(F)cc1)C(Br)CCCl
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C(c1ccc(F)cc1)C(CCN1CCOCC1)N1CCOCC1

Procedure:
A solution of 10 g. of 1-p-fluorobenzoyl-1-bromo-3-chloro-propane, 12.5 g. of morpholine and a catalytic quantity of potassium iodide in 100 cc. xylene is made to reflux for 12 hours and then cooled. The resulting solid is filtered and the filtrate extracted with dilute HCl. The separated aqueous phase is filtered hot using animal charcoal, cooled, made alkaline with dilute soda solution, and extracted with diethyl ether. The organic phases are combined, washed with water, dried and evaporated, m.p. : 82°C (from hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCCO
Yield: 92.3 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and N-(2-hydroxyethyl)-6-chlorohexanesulfonamide (487.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (915.2 mg) as a pale yellow oil (92.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH:9]1[OH:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33]C1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:11][CH2:10][CH:9]1[O:32][CH3:33])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1C(O)CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 1585 %

Procedure:
A solution of 2.92 g of 204 (6.41 mmol) in 10 ml of anhydrous MeOH was added with 100 mg of PPTS (0.40 mmol, 6.2 mole %) and stirred at RT overnight. After checking completion of the reaction by means of TLC (EE/CH 1:7), the solution was concentrated, the remaining residue taken up in 25 ml of ethyl acetate and filtered over a small amount of silica gel. The filtrate was concentrated and further purified using silica gel column chromatography (EE/CH 1:7), thereby obtaining 2.98 g of 59 (6.34 mmol, 99%) as a colorless oil.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([O:18][CH2:19][C:20](=[CH2:22])[CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[O:6]1[C:20]([CH3:21])([CH2:19][O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22]1
Reactant: C=C(C)COc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC1(COc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
To a solution of 3-chloroperoxybenzoic acid (70% pure, 4.2 g, 17 mmol) in 40 mL of chloroform was added methallyl phenyl ether (2.5 g, 16.87 mmol). The mixture was stirred at room temperature for 5 hours then worked up by pouring into ether and sodium bicarbonate. The organic phase was washed with sodium bisulfite, sodium bicarbonate, and sodium chloride, dried over anhydrous sodium sulfate and evaporated to give 2.3 g of 1,2-epoxy-2-methyl-3-phenoxypropane.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][N:26]3[C:35]=2[CH:34]=[C:33]2[C@@:28]([CH3:38])([C@@H:29]([CH:36]=[O:37])[CH2:30][CH2:31][CH2:32]2)[CH2:27]3)=[CH:19][CH:18]=1.[Cl-].[NH4+]>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][N:26]3[C:35]=2[CH:34]=[C:33]2[C@@:28]([CH3:38])([C@@H:29]([CH:36]([OH:37])[C:2]4[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=4)[CH2:30][CH2:31][CH2:32]2)[CH2:27]3)=[CH:19][CH:18]=1
Reactant: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2C=O
Reactant: COC(=O)c1ccc(I)s1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)s1
Reaction time: 1 h

Procedure:
To a stirred solution of the above methyl 5-iodothiophene-2-carboxylate (175 mg, 0.65 mmol) in anhydrous THF (2 mL) cooled in an acetonitrile-dry ice bath was added isopropylmagnesium chloride solution (2 M in THF, 0.32 mL, 0.64 mmol) dropwise under nitrogen. The reaction mixture was stirred at the same temperature for 40 min before (5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbaldehyde (Example 1g, 100 mg, 0.32 mmol) was added. After the reaction mixture was stirred at the same temperature for 1 hr, saturated aqueous ammonium chloride solution (3 mL) was added. The mixture was extracted with ethyl acetate (3×2 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (50-100% ethyl acetate in heptanes then 0-20% methanol in ethyl acetate) gave methyl 5-(((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(hydroxy)methyl)thiophene-2-carboxylate as a solid.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:30]=[C:29]([CH3:31])[C:27]([NH2:28])=[C:26]([Cl:32])[CH:25]=1.[C:33]([NH:36][C:37](=[CH2:42])[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34].C(N(CC)CC)C>C(#N)C>[C:33]([NH:36]/[C:37](=[CH:42]/[C:24]1[CH:30]=[C:29]([CH3:31])[C:27]([NH2:28])=[C:26]([Cl:32])[CH:25]=1)/[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34]
Reactant: Cc1cc(Br)cc(Cl)c1N
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C(=C\c1cc(C)c(N)c(Cl)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under protective nitrogen gas 2.02 g (9.0 mmol) palladium(II)acetate and 2.82 g (9.0 mmol) tri-o-tolylphosphine were added to a mixture of 25.0 g (113 mmol) 4-bromo-2-chloro-6-methyl-aniline, 19.9 g (136 mmol) methyl 2-acetamidoacrylate, 350 ml triethylamine and 150 ml acetonitrile at ambient temperature. The reaction mixture was stirred for 18 hours at 80° C., evaporated down under reduced pressure, the residue was combined with 600 ml dichloromethane and water and filtered off from the insoluble precipitate. The organic phase was dried over sodium sulphate, evaporated down under reduced pressure and then combined with 200 ml of ethyl acetate/cyclohexane (3/1). The insoluble fraction was suction filtered and the mother liquor was purified by column chromatography through silica gel. The corresponding fractions were evaporated down under reduced pressure and combined with the insolublen fraction suction filtered previously.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([CH3:41])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]2[C:16]2[CH:37]=[CH:38][CH:39]=[CH:40][C:15]=2[O:14][CH2:13]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][N:11]([CH3:41])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[C:17]2[C:16]2[CH:37]=[CH:38][CH:39]=[CH:40][C:15]=2[O:14][CH2:13]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl(7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in Example 1, Step 6) (0.1 M) in DCM was treated with an excess of TFA (>50 eq.). The mixture was stirred at RT for 1 h. All the volatiles were then removed in vacuo and the residue treated with a solution of HCl/Et2O (2 M) and the resulting mixture concentrated in vacuo. The product was used in the next step without further purification. (ES+) m/z 462 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[CH3:22][C:3]1[C:2]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: Cc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Cl
Reactant: OB(O)c1cncnc1
Product: Cc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 40 using 5-chloro-6-methyl-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 43.1) and pyrimidin-5-ylboronic acid. UPLC-MS (Condition 1) tR=2.10 min, m/z=375.0 [M+H]+, m/z=373.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.57 (s, 3H) 7.40 (d, J=8.80 Hz, 2H) 7.88 (d, J=9.29 Hz, 2H) 8.30 (d, J=2.20 Hz, 1H) 9.03 (s, 2H) 9.08 (d, J=2.20 Hz, 1H) 9.29 (s, 1H) 10.55 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]4[CH2:28][CH2:27][N:26]([C:29]([C@@H:31]5[CH2:35][CH2:34][CH2:33][N:32]5C(OC(C)(C)C)=O)=[O:30])[CH2:25][C:20]=4[N:21]3[CH3:24])=[CH:17][CH:16]=2)[C:11](=[O:43])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>CO.CCOCC>[ClH:44].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]4[CH2:28][CH2:27][N:26]([C:29]([C@@H:31]5[CH2:35][CH2:34][CH2:33][NH:32]5)=[O:30])[CH2:25][C:20]=4[N:21]3[CH3:24])=[CH:17][CH:16]=2)[C:11](=[O:43])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)[C@@H]1CCCN1)C2
Yield: 85 %

Procedure:
(S)-tert-Butyl 2-(7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-carbonyl)pyrrolidine-1-carboxylate (55 mg, 0.094 mmol) was stirred in a mixture of MeOH (2 mL) and 2 N HCl in Et2O (8 mL) for 5 h. The reaction mixture was concentrated to provide the title compound (42 mg, 85%) as a yellow-green solid: mp 220-226° C.; 1H NMR (500 MHz, CD3OD) δ 7.79 (dd, J=7.5, 1.4 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.49-7.46 (m, 3H), 7.44-7.46 (m, 2H), 7.39-7.36 (m, 1H), 7.04 (dd, J=8.3, 1.6 Hz, 1H), 6.57-6.55 (m, 1H), 6.34 (d, J=2.5 Hz, 1H), 5.27 (s, 2H), 4.96-4.87 (m, 2H), 3.90-8.86 (m, 2H), 3.77 (s, 3H), 3.48-3.34 (m, 3H), 3.00-2.86 (m, 2H), 2.67-2.61 (m, 1H), 2.17-2.02 (m, 3H); ESI MS m/z 483 [M+H]+; HPLC (Method B) 95.5% (AUC), tR=13.5 min.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[CH:3][C:1]#[N:2])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add diethyl cyanomethylphosphonate (5.33 g, 4.88 mL, 30.11 mmol) to potassium carbonate (3.47 g, 25.09 mmol) in dry THF (10 mL) and stir at room temperature for 15 min., then heat under reflux for 15 min. To this mixture add 4-oxopiperidine-1-carboxylic acid t-butyl ester (5.00, 25.09 mmol) and heat under reflux under nitrogen for 24 hr., allow to cool to room temperature and stand overnight. Pour the reaction mixture into aqueous potassium carbonate solution (10%, 80 mL) and extract the resultant mixture with ethyl acetate (2×50 mL). Combine the organics, dry (MgSO4) and evaporate in vacuo to give 4-cyanomethylenepiperidine-1-carboxylic acid t-butyl ester as a liquid which solidifies on standing (5.39 g, 96.6%). NMR (δ-CDCl3) 1.5 (s, 9H), 2.4 (m, 2H), 2.6 (m, 2H), 3.5 (m, 4H), 5.2 (s, 1H).