Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2([S:19][CH2:20][CH3:21])[CH2:18][CH2:17]2)([OH:15])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2([S:19]([CH2:20][CH3:21])=[O:30])[CH2:17][CH2:18]2)([OH:15])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: CCSC1(C(O)(Cc2nc[nH]n2)c2ccc(Cl)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)C1(C(O)(Cc2nc[nH]n2)c2ccc(Cl)cc2)CC1
Yield: 57 %

Procedure:
5 g (0.0155 mol) of 1-(4-chlorophenyl)-1-[1-(ethylthio)-1-cyclopropyl]-2-(1,2,4-triazol-yl)-1-ethanol (see Example 1) are stirred with 3.3 g of m-chloroperbenzoic acid (80-90% strength) in 40 ml of methylene chloride overnight at room temperature and then for one hour under reflux. Thereafter, the mixture is washed with twice 20 ml of 5% strength aqueous sodium hydroxide solution and twice with water. The organic phase is dried over sodium sulphate and evaporated down in vacuo. The residue is recrystallized from glycol monomethyl ether acetate. 3 g (57% of theory) of 1-(4-chlorophenyl)-1-[1-(ethylsulphinyl)-1-cyclopropyl]-2-(1,2,4-triazol-yl)-1-ethanol of boiling point 185° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:4](=[O:34])[C:3]1=[N:35]NC1C=CC=CC=1>C(O)(=O)C.[Zn]>[NH2:35][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)[C:4]1=[O:34]
Reactant: COc1ccc(N(C(=O)Cn2c(=O)c(=NNc3ccccc3)c(=O)n(-c3ncccn3)c3ccccc32)C(C)C)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3ncccn3)c3ccccc32)C(C)C)cc1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred solution of 2-[2,4-dioxo-3-(phenyl-hydrazono)-5-pyrimidin-2-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (500 mg, 0.886 mmol) in acetic acid (12 mL) at ambient temperature was added zinc dust (530 mg) and the resulting mixture was stirred 1 h. The zinc was separated by filtration, the filtrate concentrated in vacuo, and the resultant oil partitioned between water (30 mL) and ethyl acetate (80 mL). The pH was adjusted to 8 with 6N sodium hydroxide and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×35 mL) and the organics combined, dried with magnesium sulfate, filtered and concentrated in vacuo to give a yellow foam. The crude product was purified via flash chromatography on silica gel (15 g) eluting with methylene chloride/methanol (19:1, 250 ml). Appropriate fractions were combined and concentrated to give the title compound (255 mg, 0.537 mmol) as a white glass:
Reaction SMILES: [CH2:1]([C:3]1(O)[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1](=[C:3]1[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2)[CH3:2]
Reactant: CCC1(O)C2CC3CC(C2)CC1C3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=C1C2CC3CC(C2)CC1C3

Procedure:
70 g of 2-ethyl-2-adamantanol was dissolved in toluene, 1 g of p-toluenesulfonic acid was added, and water was removed by distillation by use of a Dean and Stark dehydrator under heating so as to obtain 2-ethylideneadamantane. To 50 g of the obtained 2-ethylideneadamantane, 500 g of methacrylic acid and 0.1 ml of concentrated sulphuric acid were added, and the resulting mixture was heated at 80° C. for 5 hours. After hexane was added to the obtained reaction mixture, the mixture was washed with water, a 5% sodium hydroxide solution, and water in turn, and it was confirmed that the pH of an aqueous phase became 8. After the washed organic phase was concentrated, unreacted 2-ethylideneadamantane was partially removed by sublimation so as to obtain crude 2-ethyl-2-adamantyl methacrylate containing 80% by weight of 2-ethyl-2-adamantyl methacrylate.
Reaction SMILES: Cl[C:2]1([CH2:10][CH:11]=[CH2:12])[C:7](=[O:8])[CH2:6][CH2:5][CH2:4]C1=O>C1(C)C(C)=CC=CC=1>[CH2:10]([C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH:4]=1)[CH:11]=[CH2:12]
Reactant: C=CCC1(Cl)C(=O)CCCC1=O
Solvent: Cc1ccccc1C
Product: C=CCC1=CCCC1=O
Reaction time: 4.5 h
Yield: 49.5 %

Procedure:
Anhydrous powdered sodium carbonate (670 g) and 1300 ml of dry (alumina) xylene were placed in a 3-l., three-necked flask equipped with a Dean-Stark trap, condenser, vibra-mixer, dropping funnel and argon inlet. The flask was flushed with argon and the contents brought to reflux. A solution of 2-chloro-2-allyl-1, 3-cyclohexanedione (147 g, 0.79 mol) in 200 ml of xylene was added dropwise at such a rate that strong refluxing was maintained. After 4.5 hr, the reaction was cooled, filtered, and the sodium carbonate cake washed thoroughly with ethyl acetate. Evaporation of the solvent and careful fractionization of the residual oil gave 47.8 g (50 percent) of 2-allyl-2-cyclopenten-1-one, bp 73°-84°/4.2 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([CH:24]=[O:25])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][C:17]([CH2:24][OH:25])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(c2ncc(C=O)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(c2ncc(CO)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To a solution of (2R)-4-(5-formyl-3-trifluoromethyl-pyridin-2-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester from step (e) above (4.48 g, 12 mmol) in methanol (30 mL) was added portionwise NaBH4 (542 mg, 14.4 mmol, Aldrich) with stirring at 0° C. The mixture was stirred at 0° C. for 30 min and the solvent was removed in vacuo. The residure was dissolved in EtOAc (60 mL) and washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 50% EtOAc/hexane to give the title compound as a gum. MS (ESI, pos. ion) m/e: 376 (M+1).
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:14][C:13]2[C:5](=[C:6]3[C:10](=[C:11]([CH3:16])[C:12]=2[CH3:15])[NH:9][C:8]([CH3:18])([CH3:17])[CH2:7]3)[CH2:4]1.Cl.[CH3:21][N:22]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:21][N:22]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2([CH3:19])[O:14][C:13]3[C:5](=[C:6]4[C:10](=[C:11]([CH3:16])[C:12]=3[CH3:15])[NH:9][C:8]([CH3:18])([CH3:17])[CH2:7]4)[CH2:4]2)[CH2:34][CH2:33]1)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1
Reactant: CN(c1nc2ccccc2s1)C1CCNCC1
Reactant: Cc1c(C)c2c(c3c1NC(C)(C)C3)CC(C)(CI)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(C)c2c(c3c1NC(C)(C)C3)CC(C)(CN1CCC(N(C)c3nc4ccccc4s3)CC1)O2
Temperature: 180 °C
Reaction time: 6 h
Yield: 56.2 %

Procedure:
A suspension of 1,6,7,8-tetrahydro-2-(iodomethyl)-2,4,5,7,7-pentamethyl-2H-furo[3,2-e]indole (372 mg, 1.0 mmol), N-methyl-N-(4-piperidinyl)-1,3-benzothiazole-2-amine hydrochloride (427 mg, 1.5 mmol) and potassium carbonate (485 mg, 3.5 mmol) in N,N-dimethylacetamide (2 mL) was stirred at 180° C. for 6 hours under the nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate two times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane-ethyl acetate 10:1), and recrystallized from ethyl acetate-hexane to obtain 276 mg of the title compound.
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1>Cl>[ClH:1].[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(CCc2ncc[nH]2)cc1
Agent: Cl
Product: O=C(O)c1ccc(CCc2ncc[nH]2)cc1
Reaction time: 16 h

Procedure:
Ester 23-4 (450 mg; 1.77 mmol) was dissolved in 6N HCl and stirred for 16 h. Concentration provided 23-5 as dark oil. Rf 0.28 (silica, 4:1:1 CH2Cl2 /MeOH/HOAc).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([CH3:18])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]#[CH:28]>CC(C)=O>[C:26]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([CH3:18])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1)#[C:27][CH3:28]
Reactant: C#CCBr
Reactant: Cc1c(-c2ccccc2)oc2cc(O)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1

Procedure:
A mixture of 7-hydroxy-3-methylflavone (2.52 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.32 g of a product with the following characteristics: m.p. 179-180° C.; 1H NMR (CDCl3) δ: 2.15 (s, 3H), 2.69 (m, 1H), 4.8 (s, 2H), 6.95-8.25 (m, 8H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:31][C:32]1[N:33]=[CH:34][C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:30])[CH2:3][CH2:4]2)=[O:9])=[CH:36][CH:37]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(Cl)nc2)CC1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 2-chloropyridine-5-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a light brown solid (19%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Brc1ccccn1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccn1
Yield: 35 %

Procedure:
With 10.0 g of 5-chloro-1H-indol-2,3-dione and 25.3 g of bromo pyridine as starting materials, 5.03 g of the title compound (orange color solid) was obtained by a similar method to Step 34-3.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:10][C@H:9]([CH:11]([CH3:13])[CH3:12])[N:8]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)=[O:16])[C:7]1=[O:28]>FC(F)(F)C(O)=O>[O:28]=[C:7]1[NH:6][CH2:10][C@H:9]([CH:11]([CH3:12])[CH3:13])[N:8]1[CH2:14][C:15]([NH:17][C:18]1[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=1)=[O:16]
Reactant: COc1ccc(CN2C[C@H](C(C)C)N(CC(=O)Nc3ccc(C(F)(F)F)nc3)C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1CNC(=O)N1CC(=O)Nc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
Trifluoroacetic acid (20 mL) was added to 2-[(5S)-3-(2,4-dimethoxybenzyl)-2-oxo-5-(propan-2-yl)imidazolidin-1-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]acetamide (900 mg), and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure, and saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford the title compound (310 mg).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Cl>CN(C=O)C.O>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[O:29][CH3:28])[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Temperature: 50 °C
Yield: 98.3 %

Procedure:
A mixture of ((S)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (2.0 g, 7.06 mmol) and cesium carbonate (3.22 g, 9.88 mmol) in DMF (40 mL) is treated with 2-methoxybenzyl chloride (1.16 g, 7.41 mmol). The reaction is heated at 50° C. for 18 h. The reaction is cooled to room temperature and diluted with water (300 mL). The white solid is collected and washed with water. The solid is dried in a 40° C. vacuum oven. After drying, 2.80 g (98%) product is obtained as a white solid. LC-ES/MS m/z 404 [M+H]+, TR=2.83 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)(=[O:15])=[O:14])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Cl[Sn]Cl>Cl.CCO>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:10]1[CH:11]=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cc(F)cc2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)Nc1cc(F)cc2cccnc12
Yield: 86.7 %

Procedure:
In a similar fashion using route 1 general procedure 4, N-(6-fluoro-quinolin-8-yl)-2-nitro-benzenesulfonamide (Intermediate 244) (520 mg, 1.49 mmol), SnCl2 (983 mg, 5.99 mmol), 6N HCl (3 drops) and EtOH (10 ml) for 4 h at 80° C. gave the title compound (410 mg, 86%) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1>O1CCCC1.C(OCC)C.[Cl-].[NH4+]>[CH2:3]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)[CH:2]=[CH2:1]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCc1ccc(F)cc1
Reaction time: 16 h

Procedure:
Allyl bromide (4.33 mL, 50 mmol) was added dropwise to a solution of 4-fluorophenyl magnesium bromide (50 mmol) in tetrahydrofuran (25 mL) and diethyl ether (25 mL). After 16 hours, the reaction suspension was diluted with diethyl ether (100 mL) and saturated aqueous ammonium chloride (50 mL). The layers were separated, and the organic layer was washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated to afford 1-allyl-4-fluorobenzene.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=[NH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[P:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:36]1([P:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:22]=[C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: N=C(Nc1ccccc1Sc1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: c1ccc(Sc2ccccc2NC(=NP(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts and modifications: 1.34 g of N1-(2-(phenylthio)phenyl)benzamidine (Amidine XIV, 4.4 mmol), 2.20 mL of 2.0 M butyllithium (4.4 mmol), 0.78 mL chlorodiphenylphosphine (4.4 mmol). After filtration to remove lithium chloride and removal of solvent, a sticky solid was isolated (2.01 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[C:4]([CH3:27])[CH:3]=1>C1COCC1.CO.[Pt](=O)=O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[C:4]([CH3:27])[CH:3]=1
Reactant: Cc1cc(F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(F)ccc1Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-fluoro-2-methylphenoxy)phenyl]-3,4-dihydropyrid o[2,1-c][1,2,4]thiadiazine 2,2-dioxide (303 mg) in THF (dry) (30 mL) and MeOH (30 mL) and the mixture was stirred at 50° C. under hydrogen for 4 hr. The starting material was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and recovered. Platinum(IV) oxide (30 mg) was added to a solution of the purified starting material in THF (dry) (30 mL) and MeOH (30 mL) and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from MeCN/IPE to give the title compound (115 mg) as colorless crystals.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:46]=[CH:45][C:14]([C:15]([C:17]2[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=3)[S:20][C:21]=2[C:22]2[N:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=2)=[O:16])=[CH:13][CH:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:16])([CH:3]2[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[C:17]2[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=3)[S:20][C:21]=2[C:22]2[N:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[N:23]=2)=[CH:45][CH:46]=1
Reactant: CC(=O)Nc1cc(-c2cc(C(=O)c3ccc(Cl)cc3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2cc(C(O)(c3ccc(Cl)cc3)C3CCN(C)CC3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Temperature: 45 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
A 25 mL round bottom flask charged with magnesium turnings (23.0 mg, 0.947 mmol) was flame-dried. To the flask was added tetrahydrofuran (1.00 mL) and a drop of 1,2-dibromoethane. The mixture was heated to 45° C. for 10 min and cooled to rt. To the mixture was added 4-chloro-N-methylpiperidine (126 mg, 0.947 mmol). The reaction was stirred at 35° C. under an atmosphere of nitrogen for 12 hrs. The mixture turned cloudy, and magnesium turnings eventually disappeared, as the reaction progressed. To a solution of N-{4-[4-(4-chlorobenzoyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide (113 mg, 0.204 mmol) in tetrahydrofuran (1.00 mL) was added the pre-prepared Grignard reagent solution dropwise at 0° C. In 3 hrs, the reaction was warmed to rt. In another 3 hrs, the reaction was quenched with water and distributed between NaHCO3(aq) saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was dried and concentrated. Purification on a silica gel column (gradient elution, 1-20% MeOH) provided N-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamide as a yellow solid (59.0 mg, 44.3% yield). LCMS: (AA) ES+ 653, 655; 1H NMR (400 MHz, CDCl3) δ 8.77-8.66 (s, 1H), 8.60-8.49 (s, 1H), 8.31-8.23 (d, J=5.3 Hz, 1H), 8.15-8.08 (m, 2H), 7.66-7.60 (s, 1H), 7.34-7.23 (m, 3H), 7.17-7.08 (d, J=8.7 Hz, 2H), 5.45-5.38 (s, 2H), 3.63-3.51 (m, 2H), 3.49-3.44 (s, 3H), 3.02-2.90 (d, J=10.8 Hz, 1H), 2.90-2.78 (d, J=11.2 Hz, 1H), 2.28-2.20 (m, 4H), 2.20-2.09 (m, 1H), 2.07-1.95 (m, 1H), 1.96-1.78 (m, 2H), 1.76-1.58 (qd, J=12.7, 3.8 Hz, 1H), 1.16-1.07 (d, J=12.5 Hz, 1H), 0.99-0.85 (m, 2H), 0.02-−0.04 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[CH3:5][C:6]([CH:8]([CH3:10])[CH3:9])=O.C1C=CC=CC=1>O>[CH:8]([C:6]1([CH3:5])[NH:1][CH2:2][CH2:3][S:4]1)([CH3:10])[CH3:9]
Reactant: NCCS
Reactant: CC(=O)C(C)C
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C1(C)NCCS1
Yield: 77.5 %

Procedure:
15.43 g (0.2 mol) of cysteamine and 29.0 g (0.2 mol) of isopropyl methyl ketone were treated with 200 ml of benzene and boiled under an inert gas atmosphere for 14 hours on a water-separator. The solution was concentrated on a rotary evaporator and filtered over 25 g of neutral aluminium oxide (activity I). The aluminium oxide was then flushed with ether. The filtrate was again concentrated and subsequently distilled under a high vacuum through a Widmer column. 22.51 g (yield 77% of theory) of 2-isopropyl-2-methyl-thiazolidine (nD20 = 1.5085) passed over in a boiling range of 40°-42° C and at a pressure of 0.009 mm Hg. IR: νmax = 1440, 1370, 790 cm-1. Odour: camphorous, woody; flavour: greenish.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5](O)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1.P(Cl)(Cl)([Cl:19])=O>CN(C)C=O>[Cl:19][C:5]1[N:6]=[C:7]2[C:12](=[C:13]3[C:4]=1[CH:3]=[C:2]([F:1])[CH:15]=[CH:14]3)[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: Oc1nc2ccccc2c2ccc(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)c(Cl)nc1ccccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a mixture of 8-fluorophenanthridin-6-ol (Example 2a, 0.15 g, 0.69 mmol) in phosphorus oxychloride (1.06 g, 0.65 mL, 6.9 mmol) was added dimethylformamide (5 mg, 5 μL), and the reaction mixture was warmed to 80° C. and stirred under nitrogen for 3 h. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was triturated with hexane, and the resulting solid isolated by vacuum filtration, washed with water, and dried to provide the title compound (0.15 g, 95% yield) which was used without additional purification.
Reaction SMILES: [OH:1][CH:2]1[CH:8]([OH:9])[CH:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[NH:6][C:5](=[O:18])[NH:4][CH:3]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CO[C:29](OC)([CH3:31])[CH3:30]>CN(C=O)C>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH:3]2[NH:4][C:5](=[O:18])[NH:6][CH:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[CH:8]3[CH:2]2[O:1][C:29]([CH3:31])([CH3:30])[O:9]3)=[CH:25][CH:24]=1
Reactant: COC(C)(C)OC
Reactant: O=C1NC(Cc2ccc(O)cc2)C(O)C(O)C(Cc2ccc(O)cc2)N1
Solvent: CN(C)C=O
Product: CC1(C)OC2C(Cc3ccc(O)cc3)NC(=O)NC(Cc3ccc(O)cc3)C2O1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Diol 2.9 (1.8 g, 5.03 mmol) was dissolved in DMF (6 mL) and 2,2-dimethoxypropane (12 mL). P-TsOH (95 mg) was added and the mixture stirred at 65° C. for 3 h. A vacuum was applied to remove water and then the mixture was stirred at 65° C. for a further 1 h. The excess dimethoxypropane was then distilled and the remaining DMF solution was then allowed to cool. The solution of acetonide 2.10 can then used without further purification in future reactions.