Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2cccc(C#N)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: N#Cc1cccc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 45A in analogy to the synthesis of the compound of Example 71A. 348 mg (68% of theory) of the title compound are obtained.
Reaction SMILES: C[C@@H](O)[C@H](O)/C(/C)=[CH:5]/[CH2:6][CH:7](/[CH:9]=[C:10]1/[CH2:11][C@@:12]([OH:20])(C)[C@H]2N(C/1)CCC2)C.C1C=C[C:27]([CH2:30][O:31]CCC#N)=[CH:26]C=1.C(#N)C=C.C(O)C1C=CC=CC=1.[AlH](CC(C)C)CC(C)C>>[CH2:12]([O:20][CH2:26][CH2:27][CH:30]=[O:31])[C:11]1[CH:5]=[CH:6][CH:7]=[CH:9][CH:10]=1
Reactant: C/C(=C\CC(C)/C=C1\CN2CCC[C@H]2[C@@](C)(O)C1)[C@@H](O)[C@@H](C)O
Reactant: N#CCCOCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: OCc1ccccc1
Solvent: C=CC#N
Product: O=CCCOCc1ccccc1

Procedure:
To generate indolizidine alcohol and aldehyde intermediates useful in the synthesis of pumiliotoxin B, it is necessary to assemble a chiral silylalkyne from esters of (S)-5-(benzyloxy)-1-trimethyl-silyl-1-pentyn-3-ol. This involves the reduction of 3-(benzyloxy)propanitrile, the latter reagent being prepared from acrylonitrile and benzyl alcohol as described by Gaiffe and Launay in Academy of Science, Serial C, Pages 1379-1380 (1968), with i-Bu2AlH to give 3-benzyloxy propanal which is condensed with ethynyllithium, prepared as described by Midland in the Journal of Organic Chemistry, Volume 40, Page 2250 (1975), to yield the racemic propargylic alcohol in about 50% yield following distillation. Reaction of the propargylic alcohol with R-(+)-2-methylbenzylamine gives the corresponding diastereomeric carbamates that upon chromatographic separation and carbamate cleavage with Cl3SiH as described by Pirkle in the Journal of Organic Chemistry, Volume 42, Page 2781 (1971) yields the (S)-alcohol and (R)-alcohol derivatives in yields of about 20%.
Reaction SMILES: [CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([O:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH:9]=1.C1C(=O)N([Br:57])C(=O)C1>C(#N)C>[CH3:49][Si:2]([CH3:48])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([O:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[C:9]=1[Br:57]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)cc1
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoate (150 mg, 0.22 mmol) was dissolved in ACN (10 mL). NBS (40 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 1 h. After concentration, the residue, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoate was used in the next step without further purification. HPLC-MS tR=3.06 min (UV254 nm); mass calculated for formula C37H46BrN5O5Si2 775.2, observed LCMS m/z 776.0 (M+H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=O.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN)(=O)=O)(C)C.[C-:30]#[N:31].[K+]>CO>[C:30]([CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)#[N:31]
Reactant: O=C1CC2CCN1CC2
Reactant: [C-]#N
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN)c(C(C)C)c1
Agent: [K+]
Solvent: CO
Product: N#CC1CN2CCC1CC2
Yield: 23.6 %

Procedure:
Quinuclidinone (24.2 g, 0.19 mol) and 2,4,6-triisopropylbenzene sulphonohydrazide (72 g, 0.24 mol) (250 ml) were stirred together in anhydrous methanol for 3 hours. Potassium cyanide (33.8 g, 0.51 mol) was added and the mixture heated under reflux for 5 hours. The material isolated, after evaporation of the solvent, was partitioned between water and dichloromethane. The organic phase was dried (sodium sulphate) and evaporated and the residue fractionally distilled under reduced pressure to give 3-cyano-quinuclidine (6.1 g), approximate b.p. 95°-100° at 13 N.m-2 (0.1 mmHg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[N:3]1.C([Li])CCC.CON(C)[C:15](=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=1.Cl>C1COCC1>[CH3:1][N:2]1[C:6]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=2)=[O:27])=[N:5][N:4]=[N:3]1
Reactant: Cn1cnnn1
Reactant: CON(C)C(=O)c1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnnc1C(=O)c1cccc(OC(F)(F)F)c1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a stirred solution of 1-methyl-1H-tetrazole (7.68 g, 91.3 mmol) in anhydrous THF (360 mL), cooled to −70° C. with an acetone/dry ice bath, was added dropwise a solution of n-butyllithium (1.6 M in hexanes, 57.1 mL, 91.3 mmol). After the addition was over, the resulting cloudy suspension was stirred for 45 min at −70° C. A solution of N-methoxy-N-methyl-3-(trifluoromethoxy)benzamide (22.3 g, 76.1 mmol) in THF (60 mL) was then added dropwise while keeping the internal temperature below −60° C. The reaction mixture was then allowed to warm up and stirred at room temperature for 18 h. The reaction mixture was poured into a mixture of ice-cold water (100 mL) and aq. HCl (1 M, 100 mL), the layers were separated, the water phase was extracted with ethyl acetate (2×150 mL), the combined organic layers were washed with water (2×200 mL) and dried (MgSO4). Purification on silica gel afforded (1-methyl-1H-tetrazol-5-yl)[3-(trifluoromethoxy)phenyl]methanone as a light yellow oil [5.12 g, yield 21%; HPLC/MS:m/z=273 (M+H); log P(HCOOH)=2.96].
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CCOCC.C(#N)C>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:31])[N:15]([CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([CH2:7][N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([N:22]([CH3:32])[CH3:21])=[CH:24][CH:25]=3)=[O:31])[CH2:13][CH2:12]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: CCCCCNC[C@H]1CC[C@H](CNCCCCC)CC1
Solvent: CCOCC
Solvent: CC#N
Product: CCCCCN(C[C@H]1CC[C@H](CN(CCCCC)C(=O)Nc2ccc(N(C)C)cc2)CC1)C(=O)Nc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Trans-1,4-bis[(normalpentylamino)methyl]cyclohexane, 0.56 g, was dissolved in 10 ml of ether. A solution of 0.81 g of 4-dimethylaminophenyl isocyanate in 20 ml of acetonitrile was added. The reaction mixture was stirred at room temperature for 10 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to provide 1.10 g (yield: 89%) of white crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][N:6]([CH3:8])[CH3:7])[CH:3]=O.CC(N)C.[NH2:14][CH2:15][CH2:16][CH2:17][Si:18]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>>[CH3:1][C:2]([CH3:9])([CH2:5][N:6]([CH3:8])[CH3:7])[CH:3]=[N:14][CH2:15][CH2:16][CH2:17][Si:18]([O:25][CH2:26][CH3:27])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CN(C)CC(C)(C)C=O
Solvent: CC(C)N
Product: CCO[Si](CCCN=CC(C)(C)CN(C)C)(OCC)OCC

Procedure:
13.57 g 2,2-dimethyl-3-dimethylaminopropanal, 7.45 g 2-propanamine and 22.14 g 3-aminopropyltriethoxysilane were reacted according to the general manufacturing procedure (iminosilanes). Yield: 32.3 g of a clear, colorless oil having an amine content of 5.97 mmol N/g and a purity of 98%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].Cl[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.O>CS(C)=O>[CH2:20]([O:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1cccs1
Reaction time: 16 h
Yield: 86 %

Procedure:
Anhydrous potassium carbonate (11.04 g.) was added to a stirred suspension of N-hydroxyphthalimide (17.12 g.) in dry dimethyl sulphoxide (200 ml.). A brown colour developed, 2-Chloromethylthiophene (28.5 g.) was added dropwise and the mixture was stirred for 16 hr., during which time the colour disappeared. The suspension was poured into water (800 ml.) and cooled to 5°. The white precipitate was filtered off, and recrystallised from ethanol to give colourless needles of N-(then-2-yloxy)phthalimide (23.4 g., 83%), m.p. 129.7°-130.9° τ values (DMSO-d6) are 4.58 (CH2), 2.28, 2.68, 2.90 (thienyl protons) 2.08 (phthalimide protons)
Reaction SMILES: [NH2:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:3]1[S:7][C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[O:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])=[N:5][C:4]=1[CH3:23].[Si:31]([O:38][C@H:39]([CH2:43]Cl)[CH2:40][CH:41]=O)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[BH4-].[Na+].C(Cl)Cl>CO.O>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:11]3([C:9]([NH:8][C:6]4[S:7][C:3]([CH:2]([N:1]5[CH2:41][CH2:40][C@H:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[CH2:43]5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[Cl:30])=[C:4]([CH3:23])[N:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCl)CC=O
Reactant: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(N)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(c1ccccc1Cl)N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 3 h

Procedure:
To a solution of N-(5-(amino(2-chlorophenyl)methyl)-4-methylthiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (Isomer A) (450 mg, 1.02 mmol) in MeOH (5 mL) was added (S)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (289 mg, 1.22 mmol). The reaction mixture was stirred at room temperature for 20 min before NaBH4 (58 mg, 1.53 mmol) was added. Stirring was continued at room temperature for 3 h. After approximately 1 h some precipitate/gum started to form in the reaction solution so MeOH (5 mL) and CH2Cl2 (2 mL) were added to keep everything in solution. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers was washed with brine, dried over MgSO4 and concentrated. The residue was adsorbed onto silica gel and purified by column chromatography (0-25% EtOAc/hexanes) to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(((S)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chlorophenyl)methyl)-4-methylthiazol-2-yl)cyclopropanecarboxamide (Isomer A) as a pale yellow solid (470 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.83 (dd, J=8.1, 1.6 Hz, 1H), 7.28-7.25 (m, 2H), 7.13 (m, 1H), 6.88-6.83 (m, 2H), 6.79 (d, J=7.9 Hz, 1H), 6.00 (s, 2H), 5.08 (s, 1H), 4.33 (m, 1H), 2.94 (dd, J=9.9, 6.3 Hz, 1H), 2.67 (td, J=8.3, 3.4 Hz, 1H), 2.53 (q, J=8.4 Hz, 1H), 2.37 (s, 3H), 2.17 (dd, J=9.9, 4.7 Hz, 1H), 2.00 (m, 1H), 1.74-1.61 (m, 3H), 1.17 (m, 2H), 0.86 (m, 9H), 0.01 (s, 3H), −0.01 (s, 3H); HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; ESI-MS 626.5 m/z (MH+).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:20]=[C:21]([CH2:28][OH:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=1[OH:25].C(OCC)(=O)C>C(Cl)Cl>[OH:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([C:1]#[C:2][C:19]3[CH:20]=[C:21]([CH2:28][OH:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=3[OH:25])([CH3:17])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:16]
Reactant: COc1cc(CO)cc(I)c1O
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(CO)cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)c1O

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 3-iodo-4-hydroxy-5-methoxybenzenemethanol [P. Claus et al. Monatsh. Chem. 103, 1178 (1972)]under the conditions described in Example 1. The product was isolated by chromatography over silica gel using 30 % (V/V) of ethyl acetate in methylene chloride. Crystallization from ether/ hexane yielded colorless crystals with m.p. 160°-163°.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(OC(Cl)=O)C.[NH2:20][CH:21]1[CH2:25][N:24]([CH3:26])[N:23]([CH3:27])[CH2:22]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:20][CH:21]2[CH2:25][N:24]([CH3:26])[N:23]([CH3:27])[CH2:22]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CN1CC(N)CN1C
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CN(C)N(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of equal molar amounts of 4-amino-5-chloro-2-methoxybenzoic acid and triethylamine in methylene chloride (0°-5° C.) was treated dropwise with a slight excess of ethylchlorocarbonate. After 1.0 hour a solution of 4-amino-1,2-dimethylpyrazolidine in methylene chloride was added and the mixture stirred for about two hours at room temperature. An aqueous solution of sodium bicarbonate was added to the reaction mixture, the organic phase separated and concentrated to give the product which melted at 169°-171° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.[Si:20](OS(C(F)(F)F)(=O)=O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:11][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])([CH3:9])[CH3:10])=[N:6][CH:7]=1
Reactant: CC(C)(O)c1ccc(Br)cn1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCl
Product: CC(C)(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(5-bromopyridin-2-yl)propan-2-ol (1.20 g, 5.55 mmol, prepared according to the method in Tetrahedron Lett. 2000, 41, 4335) and 2,6-lutidine (1.29 mL, 11.11 mmol) in CH2Cl2 (12 mL) was added TBSOTf (1.91 mL, 8.33 mmol). After stirring at room temperature for 2 h, the reaction was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered, and evaporated. The crude residue was purified on silica gel (0-10% EtOAc/hexanes) which afforded the title compound as a colorless oil.
Reaction SMILES: C(S)CCCCCCCCCCC.CC([O-])(C)C.[K+].[CH2:20]([N:27]1[CH2:32][CH2:31][O:30][CH:29]([C:33]2[CH:38]=[CH:37][C:36]([O:39]C)=[CH:35][C:34]=2[Cl:41])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[CH2:20]([N:27]1[CH2:32][CH2:31][O:30][CH:29]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][C:34]=2[Cl:41])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)CCO2)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: CCCCCCCCCCCCS
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1ccc(C2CN(Cc3ccccc3)CCO2)c(Cl)c1
Temperature: 110 °C
Reaction time: 6 h
Yield: 85.2 %

Procedure:
To a solution of 1 dodecanethiol (12.7 mL; 52.86 mmol) in dry DMF (50 mL), was added KOtBu (5.93 g; 52.86 mmol) at 0° C. After complete addition the mixture was allowed to slowly come to RT (˜30 min), and then 4-benzyl-2-(2-chloro-4-methoxy-phenyl)-morpholine (5.60 g; 17.62 mmol) was added. The resulting mixture was stirred at 110° C. for 6 hours. After cooling to RT, EtOAc was added and the resulting mixture was washed with 5% aqueous NaHCO3, water and brine; dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2CL2/MeOH 99:1) to afford 4-(4-benzyl-morpholin-2-yl)-3-chloro-phenol (4.56 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH2:10][C:11]1([CH2:19][C:20]#[C:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13][CH2:12]1.CCOC(C)=O.CCCCCC>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:8]=[C:9]1[CH2:10][C:11]3([CH2:12][O:13][C:14]([CH3:18])([CH3:17])[O:15][CH2:16]3)[CH2:19][C:20]1=[C:21]2[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC1(C)OCC(CC#CC(=O)C(C)(C)C)(CC=Cc2ccccc2Cl)CO1
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1Cl
Solvent: CCCCCC
Product: CC1(C)OCC2(CO1)Cc1cc3c(Cl)cccc3c(C(=O)C(C)(C)C)c1C2
Yield: 47 %

Procedure:
To a 10-20 mL microwave irradiation vial equipped with a stir bar was added compound 4b (0.21 g, 0.54 mmol) in 1,2-dichlorobenzene (10 mL). The reaction was irradiated with stirring at 180° C. for 45 min until complete by TLC (AcOEt/n-hexane 2:8). The solution was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene and then AcOEt/n-hexane 2:8 to collect the pure product. The title compound was isolated as a light yellow solid in a 47% yield (0.098 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[NH4+:38].[OH-]>O1CCOCC1>[NH2:38][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=3[F:36])(=[O:28])=[O:29])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1
Temperature: 100 °C
Yield: 35 %

Procedure:
In a pressure vessel was placed N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (300 mg, 0.513 mmol) and NH4OH (2 mL) and 1,4-dioxane (2 mL) were added. The vessel was sealed and heated at 100° C. for 18 h. The reaction mixture was cooled, concentrated onto silica and the residue was column chromatographed to give the title compound (0.10 g, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (br. s., 1H), 7.81 (d, J=5.3 Hz, 1H), 7.62-7.73 (m, 1H), 7.39-7.52 (m, 2H), 7.28-7.34 (m, 1H), 7.21 (t, J=9.1 Hz, 2H), 6.55 (s, 2H), 5.44 (d, J=5.3 Hz, 1H), 3.70 (t, J=4.7 Hz, 4H), 3.44 (t, J=4.6 Hz, 4H). MS (ES+): 566 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[N:17]#[C:18][NH2:19].CC(C)([O-])C.[K+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([N+:37]([O-:39])=[O:38])[CH:31]=1)=[O:29]>C(#N)C.O>[NH2:17][C:18]1[N:19]=[C:2]([NH:1][C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)=[CH:8][CH:9]=2)[S:3][C:27]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([N+:37]([O-:39])=[O:38])[CH:31]=1)=[O:29]
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N#CN
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a mixture of 1-(4-isothiocyanatophenyl)-4-methylpiperazine (of Example 1; 1.0 g, 4.3 mmol) and cyanamide (0.2 g, 4.8 mmol) in acetonitrile (43 mL), a solution of potassium tert-butoxide (43 mL, 0.1 M in tert-BuOH) was added. After 30 minutes at room temperature, 2-bromo-1-(4-chloro-3-nitro-phenyl)ethanone (1.2 g, 4.3 mmol) (Maybridge Chemical Company Ltd.) was added. The reaction mixture was stirred for 4 h and then poured into 50 mL of water. The product was collected by filtration, washed with water and diethyl ether. The yellow powder was dried in vacuo to provide 0.9 g (45% yield) of [4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-chloro-3-nitrophenyl)methanone.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[CH:14]=O)[CH2:3][CH2:2]1.[C:16]([O:20][C:21](=[O:42])[NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:41])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH3:37])=[C:32]([N+:38]([O-])=O)[CH:31]=2)[CH2:24]1)([CH3:19])([CH3:18])[CH3:17].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.C(Cl)Cl>[C:16]([O:20][C:21](=[O:42])[NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([C:30]2[CH:35]=[CH:34][C:33]3[N:36]([CH3:37])[C:14]([C:6]4[N:5]([CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:9]5=[N:10][CH:11]=[CH:12][CH:13]=[C:8]5[CH:7]=4)=[N:38][C:32]=3[CH:31]=2)=[O:41])[CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cc2cccnc2n1CC1CC1
Reactant: CNc1ccc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(-c2cc3cccnc3n2CC2CC2)nc2cc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A solution of 1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (2 g, 8.99 mmol) in ethanol (90 mL) was added to a round bottom flask containing (R)-tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (3.4 g, 8.98 mmol) and the resulting solution stirred at room temperature. A solution of sodium dithionite (3.14 g, 15.33 mmol) in water (45 mL) was added portionwise to the reaction mixture. The reaction mixture was heated to 100° C. and stirred under nitrogen for 4 hours. The reaction mixture was concentrated under vacuum then diluted with DCM (150 ml) and water (150 ml). The organic layer was collected and the aqueous layer washed with DCM (3×100 ml). Organic layers were collected and backwashed with water (2×100 ml). The organic layer was collected, dried with Na2SO4, filtered through a hydrophobic frit and concentrated under vacuum to yield a crude product. This was dissolved in a minimum volume of DCM and purified using Biotage SP4 on a 100 g SNAP silica cartridge. The column was eluted with a gradient of 70-100% ethyl acetate in DCM for 10CV. Appropriate fractions were collected and concentrated under vacuum. This was dried under vacuum to yield the title compound as a yellow solid (1.867 g).