Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[NH:12][CH2:11][CH2:10][N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:12]1[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:13]1=[O:14])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)C(c2ccc(F)cc2)C1=O
Reaction time: 16 h

Procedure:
A solution of (±)-tert-butyl 2-(4-fluorophenyl)-3-oxopiperazine-1-carboxylate (50.0 mg, 0.170 mmol, described in Intermediate 48) and sodium hydride (8.15 mg, 0.204 mmol, 60% dispersion in mineral oil) in DMF (1 mL) was stirred at ambient temperature for 0.5 h. Ethyl bromoacetate (0.023 mL, 0.204 mmol) was added and stirring continued for 16 h. The reaction mixture was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were neutralized with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=381 (M+1).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([OH:24])[CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:9][CH:8]=1.C(N(CC)CC)C.[OH-].[K+]>ClCCl.C(O)(C)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:14][N:15]([C@@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[C:3](=[O:4])[CH2:2][O:24]2)=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@@H](NC[C@@H](O)c1ccc(Br)cc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)OCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A solution of chloroacetyl chloride (24.3g, 215 mmol) in dichloromethane (100 ml) was dropped into the ice-cooled solution of (1S)-1-(4-bromophenyl)-2-((1R)-1-phenylethylamino)ethanol (62.6 g, 215 mmol) and triethylamine (21.8 g, 215 mmol) in dichloromethane (600 ml) over 30 minutes and stirred for one hour at the same temperature. Resulting solution was washed with 0.5 M hydrochloric acid, saturated sodium hydrogen carbonate, brine and dried over anhydrous magnesium sulfate. The solvents were removed under reduced pressure and potassium hydroxide (85%, 16.1 g, 244 mmol) was added to a solution of resulting pale brown oil in isopropyl alcohol (600 ml) and stirred for 16 hour. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 0.5 M hydrochloric acid, saturated sodium hydrogen carbonate, brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure furnished (6S)-6-(4-bromophenyl)-4-((1R)-1-phenyethyl)morpholin-3-one (70.2 g) as a brown oil.
Reaction SMILES: [C:1]1(O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=1.COC.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N>CO>[C:12]1([NH:18][N:19]=[C:1]2[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC1=NCCCCC1
Reactant: NNc1ccccc1
Agent: COC
Agent: N
Solvent: CO
Product: c1ccc(NN=C2CCCCCN2)cc1
Yield: 45.3 %

Procedure:
When a mixture of 127 g (1 mole) of caprolactim-methylether and 108 g (1 mole) of phenylhydrazine was heated from 140° to 200°C over the course of 6 hours, 34 g (theoretically 32 g of methanol) of a distillate with a pungent smell of ammonia passed over at boiling point 60° to 140°C. The distillation of the reaction product yielded, in addition to a first runnings of starting material and 35 g of distillation residue, 92 g of caprolactam-phenylhydrazone of boiling point 125°C/0.1 mm Hg, in the form of a yellow crystalline mass which assumed a resinous brown discoloration in air. The yield was only 45.5% of theory.
Reaction SMILES: C[C@H:2](N(C)C)[C@H:3]([OH:10])C1C=CC=CC=1.CCN(CC)CC.[CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:22][C:23]#[CH:24].C(=O)C>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2].C1(C)C=CC=CC=1>[C:25]1(/[CH:21]=[CH:22]/[C:23]#[C:24][C@@H:3]([OH:10])[CH3:2])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#CC=Cc1ccccc1
Reactant: C[C@@H]([C@H](O)c1ccccc1)N(C)C
Agent: CC=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@H](O)C#C/C=C/c1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A flask containing Zn(OTf)2 (Zinc triflate purchased from Fluka was found to give the best results, other vendor's proved inefficient; 557 mg, 1.50 mmol) and (−)—N-methylephedrine (275 mg, 1.50 mmol) was added toluene (1.5 mL) and Et3N (209 μL, 1.50 mmol) at 23° C. under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 23° C. before but-1-en-3-ynyl-benzene (192 μL, 1.50 mmol) was added in one portion. After stirring for 15 min at 23° C., the reaction was cooled to 0° C., then acetaldehyde (168 μL, 30.0 mmol) was added at the same temperature in one portion. The resulting mixture was warmed to 23° C. and stirred for 35 h, then quenched by the addition of saturated aqueous NH4Cl (3 mL). The mixture was poured into a separatory funnel and diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (0→20% EtOAc/hexanes) afforded compound 7 (106 mg, 41%, 72% ee; the ee was determined after making the acetate ester) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH2:31][OH:32])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[CH2:31][O:32][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)nc3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to those described for E1 starting from 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10](Br)[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[C:18]([C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][NH:7]2)=[C:3]([O:2][CH3:1])[CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14]
Reactant: COc1cc(Br)cc2[nH]ccc12
Reactant: CCOC(=O)C=Cc1ccccn1
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1cc(OC)c2cc[nH]c2c1)c1ccccn1

Procedure:
3-(4-Methoxy-1H-indol-6-yl)-3-pyridin-2-yl-acrylic acid ethyl ester CLXXIV was prepared from 4-methoxy-6-bromo-1H-indole and 3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:20].[CH2:21]([N:23]([CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[CH3:22]>O1CCCC1>[CH2:35]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=4)=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:20])=[CH:32][CH:33]=1)[CH3:36]
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3cc(-c4cccc(OC)c4)ccc32)cc1
Temperature: 25 °C

Procedure:
The named compound is prepared by refluxing 0.020 gms E & Z 3-Hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (see example 268) with 0.0327 gms 4-(3-diethylamino-propoxy)-phenylamine (used in the preparation of Example 214) in tetrahydrofuran (0.33 mL) for 36 h. Following cooling to room temperature, solvent evaporation in vacuo, trituration with ethyl acetate/(min) hexanes and filtration the reaction yields the named compound as a solid in the amount of 9.0 mg.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.C(N(CC)CC)C>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:3]([CH3:12])[CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Temperature: 100 °C
Yield: 38.7 %

Procedure:
A stirred solution of methyl 4-bromo-3-methylbenzoate (EP 0533268 A1) (1.0 g, 0.0044 mole) in dry DMF (10 ml) under argon was treated with 4-boronobenzoic acid (0.73 g, 0.0044 mole) and tetrakis (triphenylphosphine)palladium(0) (80 mg), followed by triethylamine (1.8 ml, 0.016 mole). The mixture was heated at 100° C. for 18 hours, then concentrated in vacuo. The residue was treated with ethyl acetate and extracted with 10% NaHCO3 solution. The basic extract was acidified with dil. HCl and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a white solid (0.46 g, 39%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6](=O)[NH:5][C:4]2[CH:10]=[CH:11][CH:12]=[N:13][C:3]1=2.P(Cl)(OCC)(OCC)=O.[N+:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[C-:24].C(O)(=O)C>CN(C)C=O>[CH3:1][N:2]1[C:3]2[N:13]=[CH:12][CH:11]=[CH:10][C:4]=2[N:5]2[CH:24]=[N:23][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:6]2[C:7]1=[O:8]
Reactant: Cn1c(=O)c(=O)[nH]c2cccnc21
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CCOP(=O)(Cl)OCC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c1c(=O)n(C)c1ncccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-4-methyl-2,3-dioxo-pyrido(2,3-b)-pyrazine (5g) in 50 ml of dry dimethyl formamide (DMF) was added potassium-t-butylate (4 g). The mixture was allowed to stir at room temperature for 15 min whereafter it was cooled to -25° C. and charged with diethyl chlorophosphate (5ml). Stirring continued at 0° C. for 15 min, then it was cooled to -20° C. whereafter a preformed -30° C. cold solution of ethyl isocyanoacetate (3.9ml) and pottasium-t-butylate (4 g) in 30ml of dry DMF was added. The resulting solution was allowed to obtain room temperature before acetic acid was added (1,5 ml). The DMF was removed by evaporation in vacuo, whereafter the residue was treated with water to give the crude title compound as pale crystals. Recryst in 96% ETOH M.p. 233°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=CN=C(NNC(OC(Cl)(Cl)Cl)=O)C=2C2C=CC=CC=2)=CC=1.Cl[CH2:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:62])[F:61])=[N:58][CH:59]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:53][C:54]4[CH:59]=[N:58][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:56][CH:55]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=c1[nH]nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Agent: O=C(NNc1ncnc(-c2ccc(Cl)cc2)c1-c1ccccc1)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Temperature: 60 °C

Procedure:
To a stirred solution of 7-(4-chlorophenyl)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one and/or trichloromethyl 2-(6-(4-chlorophenyl)-5-phenylpyrimidin-4-yl)hydrazinecarboxylate (32.2 mg, 0.10 mmol) in DMF (2 mL) at room temperature under argon was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (29.4 mg, 0.15 mmol), followed by K2CO3 (27.6 mg, 0.20 mmol). The resulting mixture was heated at 60° C. for 1 h. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes, then lyophilized from 1,4-dioxane, to obtain the title compound (18.3 mg) as an off-white lyophilate. HPLC/MS: retention time=3.90 min, [M+H]30 =482. 1H NMR (CDCl3): δ 8.80 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 7.94 (dd, J=7.9, 1.5 Hz, 1H), 7.69 (d, J=7.9 Hz, 2H), 7.28-7.47 (m, 7H), 7.20 (d, J=7.2 Hz, 2H), 5.22 (s, 2H). N-alkylation, rather than O-alkylation, was demonstrated by the presence of a 13C NMR resonance at 46.8 ppm.
Reaction SMILES: [CH3:1][N:2]1[C:10]([NH2:11])=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:3]1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[CH3:1][N:2]1[C:10]([NH:11][C:21]([NH:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[S:22])=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:3]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cn1nc2c(c1N)CCCC2
Solvent: CC(C)=O
Product: Cn1nc2c(c1NC(=S)NC(=O)c1ccccc1)CCCC2
Temperature: 60 °C

Procedure:
To a solution of compound 17 (5.0 g, 33.1 mmol) in 40 mL of acetone at 0° C. was added dropwise benzoyl isothiocynate (5.4 g, 33.1 mmol). The reaction mixture was gradually warmed up and stirred in an oil bath of 60° C. until TLC indicated there was no starting material remained. Concentration of the reaction mixture on rotavapor gave a yellow solid, which was further recrystallized in ethyl acetate to yield the desired product 18.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13](OCC)=[O:14])=[CH:11][C:10]2[CH:9]3[CH2:18][CH:6]([CH2:7][CH2:8]3)[C:5]1=2.C[O-].[Na+]>C(O)C>[CH:6]12[CH2:18][CH:9]([CH2:8][CH2:7]1)[C:10]1[CH:11]=[C:12]3[N:4]([CH2:3][CH2:2][NH:1][C:13]3=[O:14])[C:5]2=1
Reactant: CCOC(=O)c1cc2c(n1CCN)C1CCC2C1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NCCn2c1cc1c2C2CCC1C2
Temperature: 65 °C
Yield: 54.9 %

Procedure:
To a solution of ethyl 3-(2-aminoethyl)-3-azatricyclo[5.2.1.02,6]deca-2(6),4-diene-4-carboxylate (334e) (1.8 g, 7.2 mmol) in ethanol (40 mL) was added sodium meth-oxide (2.5 g, 36 mmol). The mixture was heated at 65° C. for 12 hours. It was then cooled to room temperature. The solvent was evaporated to dryness. The residue was purified by column chromatography eluting with 20:1 methylene chloride/methanol to give 334f as a brown solid (800 mg, 53%). MS: [M+H]+ 203.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:10])=[NH:9].C[O:12][CH:13]=[C:14]([C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15](OC)=O.C(N(CC)CC)C>CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:10]=[C:13]([OH:12])[C:14]([C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][N:9]=1
Reactant: COC=C(C#C[Si](C)(C)C)C(=O)OC
Reactant: N=C(N)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(-c2ccccn2)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of compound 37-b (15 g, 71 mmol), compound 37-h (12.2 g, 77.8 mmol), triethylamine (21.4 g, 212 mmol) in methanol (200 mL) was stirred overnight at room temperature. The residue obtained from removal of the solvent was purified by flash chromatography (DCM) to afford compound 37-i (7.5 g, 39%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.668-8.649 (m, 1H), 8.428-8.395 (m, 1H), 8.257 (s, 1H), 7.937-7.880 (m, 1H), 7.517-7.471 (m, 1H), 0.285 (s, 9H). LC-MS (ESI): 270 [M+H]+
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[C:7]([NH:31][C:32](=[O:34])[CH3:33])([CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=2)[CH2:14]1)[C:8](OCC)=[O:9])C>C1COCC1.C(OCC)(=O)C>[OH:9][CH2:8][C:7]([NH:31][C:32](=[O:34])[CH3:33])([CH2:6][OH:5])[CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=2)[CH2:14]1
Reactant: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCc1ccc2c(c1)CCC(C(CO)(CO)NC(C)=O)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
Lithium borohydride (2M solution in THF, 0.88 ml, 1.76 mmol) was added to compound 6 (200 mg, 0.44 mmol) in 5 ml THF at 0° C. The reaction mixture was stirred at room temperature for 48 hours and diluted with 40 ml ethyl acetate. The solution was washed with brine (2×20 mL) and dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, 4% MeOH in CH2Cl2) to provide 55 of mg compound 7 (33%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[CH:8]=[C:7]([CH:9]=O)[NH:6][CH:5]=1>>[CH2:1]([NH:3][CH2:9][C:7]1[NH:6][CH:5]=[N:4][CH:8]=1)[CH3:2]
Reactant: O=Cc1cnc[nH]1
Reactant: CCN
Product: CCNCc1cnc[nH]1

Procedure:
prepared by reaction of ethylamine with 3H-imidazole-4-carbaldehyde
Reaction SMILES: [CH:1]1([Ti:6]([Cl:9])(Cl)Cl)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:10]1([N:16]=[CH:17][C:18]([CH3:26])=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Mg]>C1COCC1>[Cl:9][Ti:6]1([CH:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]([CH3:26])=[CH:17][N:16]1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C=NC1CCCCC1)=Cc1ccccc1
Reactant: Cl[Ti](Cl)(Cl)C1C=CC=C1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1=CN(C2CCCCC2)[Ti](Cl)(C2C=CC=C2)C1c1ccccc1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a solution of 5 g (22.79 mmol) cyclopentadienyltitanium(IV) chloride in 100 ml THF were added 5.18 g (22.79 mmol) 1-cyclohexyl-3-methyl-4-phenyl-1-aza-buta-1,3-diene and 0.55 g magnesium and the mixture was stirred at room temperature until the metal was fully reacted. The solvent was then removed to dryness in vacuo and the residue was extracted with 50 ml diethyl ether. 4.36 g 2-chloro-2-cyclopentadienyl-1-cyclohexyl-4-methyl-3-phenyl-1-aza-2-titana-cyclopent-4-ene were isolated from the diethyl ether extract as dark brown crystals. (51% yield, characterised by 1H-NMR, 13C-NMR and elemental analysis).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.COC(Cl)=O.[Cl:19][C:20]1[C:33]2[S:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[CH:23]=[CH:22][C:21]=1O>C1COCC1.O>[Cl:19][C:20]1[C:33]2[S:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[CH:23]=[CH:22][C:21]=1[O:5][C:1](=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: Oc1ccc2c(c1Cl)Sc1ccccc1N2
Agent: COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Temperature: 5 °C
Reaction time: 12 h

Procedure:
To a solution of iso-butyric acid (1.6 ml) in THF (10 ml) at 0° C. was added Et3N (2.7 ml) and methylchloroformate (1.5 ml). To this resulting suspension was added slowly at 0° C. a solution of 4-chloro-3-hydroxy-10H-phenothiazine in THF (10 ml). The reaction mixture was stirred at 5° C. for 12 hours, after which H2O was added and the resulting aqueous phase extracted with ethyl acetate. The organic layer was then dried and evaporated. The resulting residue was purified by chromatography on silica gel to give 2.25 g of 4-chloro-3-isobutyryloxy-10H-phenothiazine (m.p. 155° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=S)[CH2:8][O:7][C:6]=2[N:12]=1.C([O:21][C:22]([NH:24][NH2:25])=O)C>CC1C=CC(C)=CC=1>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]3[C:22](=[O:21])[NH:24][N:25]=[C:9]3[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: S=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: CCOC(=O)NN
Solvent: Cc1ccc(C)cc1
Product: O=c1[nH]nc2n1-c1cc(-c3ccccc3)c(Br)nc1OC2
Temperature: 180 °C
Yield: 27.3 %

Procedure:
In a 10 ml microwave vial was 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-thione (1 g, 3.11 mmol) and ethylhydrazine carboxylate (1.2 g, 12.44 mmol) in p-xylene (10 ml) to give a yellow suspension. The reaction mixture was heated to 180° C. for 45 minutes under microwave conditions. The crude residue was concentrated under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 100% ethyl acetate in n-hexane) to give the title compound (293 mg, 27%). LCMS (Method D) RT 1.069 min, M+1=346.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([CH2:19][N:20]=[C:21]=[S:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:21]([NH:20][CH2:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[S:22])(=[O:10])=[O:11]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: S=C=NCC1CCCCC1
Agent: Cl
Product: Nc1cc(Cl)sc1S(=O)(=O)NC(=S)NCC1CCCCC1
Yield: 8 %

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and cyclohexylmethyl isothiocyanate by a procedure analogous to the procedure described in example 3-a; a syrup was obtained (yield 8%), 1H-NMR (DMSO-d6): δ0.95 (m, 2H), 1.25 (m, 3H), 1.70 (m, 6H), 3.45 (d, 2H, CH2), 4.45 (br, HDO+NH), 6.65 (s, 1H, H4).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[O:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[O:18]1[CH2:19][CH2:20][N:21]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:13]3[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=4)[CH:16]=[N:15][CH:14]=3)=[CH:32][CH:33]=2)(=[O:26])=[O:25])[CH2:22][CH2:23]1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Reactant: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)n2)c1
Reaction time: 16 h
Yield: 31.2 %

Procedure:
Using Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 4-(morpholinosulfonyl) aniline (84.8 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. and kept for 16 hours. The same workup as for Method L followed by column chromatography afforded 34 mg of title compound. Yield: 31.2%. 1H NMR (250 MHz, DMSO-d6) δ 2.11 (s, 3 H), 2.86-2.89 (m, 4 H), 3.62-3.65 (m, 4 H), 7.45 (t, 1 H, 7.8 Hz), 7.54 (d, 1 H, 8.1 Hz), 7.73-7.80 (m, 3 H), 8.14 (d, 2 H, 8.9 Hz), 8.28 (s, 1 H), 8.57 (bs, 1 H), 8.61 (s, 1 H), 10.13 (s, 1 H), 10.18 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.19, 45.90, 65.28, 117.09, 117.50, 120.06, 121.09, 125.43, 129.22, 129.33, 131.54, 134.02, 136.56, 140.07, 145.24, 147.83, 150.66, 168.57; m/z 454.2 [(M+H)+, calcd for C22H23N5O4S 453.2].