Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1OC(C2(C(N=[N+]=[N-])=O)CN(C3C=CC=CC=3)N=C2)=CC=1)([O-])=O.[N+:25]([C:28]1[O:32][C:31]([C:33]2[C:37]([N:38]=C=O)=[CH:36][N:35]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:34]=2)=[CH:30][CH:29]=1)([O-:27])=[O:26].[ClH:47]>O1CCOCC1>[ClH:47].[NH2:38][C:37]1[C:33]([C:31]2[O:32][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)=[N:34][N:35]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:36]=1
Reactant: O=C=Nc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: Cl
Agent: [N-]=[N+]=NC(=O)C1(c2ccc([N+](=O)[O-])o2)C=NN(c2ccccc2)C1
Solvent: C1COCCO1
Product: Nc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 8 h
Yield: 88 %

Procedure:
To prepare the starting material, heat 1 g of 4-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid azide in 15 ml of absolute dioxane for 1 hour at 90° C. After gas formation has finished, add the solution of the produced [3-(5-nitro-2-furyl)-1-phenyl-4-pyrazolyl]isocyanate dropwise to 4 ml of concentrated hydrochloric acid and then stir the resulting admixture overnight at from 40° to 45° C. Cool the thus-prepared material and draw off the formed precipitate to obtain 4-amino-3-(5-nitro-2-furyl)-1-phenylpyrazole hydrochloride [m.p. 211° to 213° C (with decomposition)] with the yield of 88%.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[C:9]([O:13][C:14](=[O:44])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[C:19]([C:28]2[CH:37]=[C:36]3[C:31]([C:32]([CH3:42])([CH3:41])[CH2:33][C:34](=[O:40])[N:35]3[CH2:38][CH3:39])=[CH:30][C:29]=2[CH3:43])[CH:18]=1)([CH3:12])([CH3:11])[CH3:10]>CS(C)=O>[C:9]([O:13][C:14]([CH:15]1[CH2:2][CH:16]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[C:19]([C:28]2[CH:37]=[C:36]3[C:31]([C:32]([CH3:42])([CH3:41])[CH2:33][C:34](=[O:40])[N:35]3[CH2:38][CH3:39])=[CH:30][C:29]=2[CH3:43])[CH:18]=1)=[O:44])([CH3:11])([CH3:10])[CH3:12]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C4CC4C(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Temperature: -10 °C
Reaction time: 0.58 h

Procedure:
To a round bottom flask was added trimethylsulfoxonium iodide (2.8 mmol, 0.37 g) and 60% NaH (2.8 mmol, 0.07 g) and the flask was cooled to −10° C. with an ice-water bath. DMSO 92 ML) was then added dropwise. Initially some foamy suspension was observed. The cooling bath was removed and the reaction mixture was allowed to stir at r.t. for 30-40 min till the reaction mixture became a turbid solution. Compound 2B (0.17 mmol, 0.085 g) was then dissolved in 1.5 mL DMSO and was added to the reaction mixture. The golden yellow solution was stirred at 50° C. (oil bath) for 2 h. After cooling to r.t., the reaction mixture was poured into 50 mL of ice-water. It was extracted with EtOAc (3×15 mL). The organic layer was washed with water followed by brine and was then dried over Na2SO4. The solvent was filtered and evaporated in vacuo to obtain 2-[3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-phenyl]-cyclopropanecarboxylic acid tert-butyl ester as a colorless oil. It was purified by preparative TLC with 3.5:1 hexanes-EtOAc as the eluting system to obtain 0.04 g of the product as a white foam. The product has the same Rf as the starting material. However, the product does not stain with KMnO4 stain indicating the disappearance of the double bond while the starting material does.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Yield: 83 %

Procedure:
Methyl 5-bromo-2-(4-trifluoromethoxy-benzenesulfonylamino)benzoate (0.854 g, 0.019 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL)/water (10 mL). A solution of sodium hydroxide (50%, 5 mL) was added and the mixture was heated to reflux for 2–3 hours. The tetrahydrofuran was removed by rotary evaporation and the mixture was acidified with aqueous HCl (2 M). The mixture was extracted with ethyl acetate (20 mL). The organic solvent was removed to dryness. The residue was dried azeotropically by dissolution in ethyl acetate followed by evaporation (3×15 mL). This provided an oil, which was triturated in hexane (20 mL) until a solid formed. The solid was collected by filtration and dried in a vacuum oven at 40° C. Recovery=0.691 g (83% yield). M/Z of (M−H)−=432, 1H NMR (DMSO) δ=7.42–7.48 (1H), 7.55–7.6 (2H), 7.74–7.8 (1H), 7.92–8.0 (3H), 11,2 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][N:5]=[C:4]([Cl:10])[CH:3]=1.C[N+]1([O-])CC[O:15]CC1>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH:8]=[O:15])=[CH:6][N:5]=[C:4]([Cl:10])[CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: Clc1cc(Br)c(CBr)cn1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1cnc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask was charged with 4-bromo-5-(bromomethyl)-2-chloropyridine (490 mg, 1.72 mmol), powdered 4 Å molecular sieves, and NMO (2.19 g, 18.74 mmol) then diluted with ACN (17 mL) and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-20% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C6H4BrClNO 219.9 (M+H+); Found: 220.0 (M+H+).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12](O)=[O:13])=[CH:3][CH:2]=1.S(Cl)(Cl)=O.O.[NH2:29][C:30]1[NH:34][N:33]=[N:32][N:31]=1.C(N(CC)CC)C>CN(C=O)C.O1CCCC1.ClCCl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:29][C:30]2[NH:34][N:33]=[N:32][N:31]=2)=[O:13])=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(COc2ccc(-c3ccccc3)cc2)c1
Reactant: Nc1nnn[nH]1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cccc(COc2ccc(-c3ccccc3)cc2)c1
Yield: 49.9 %

Procedure:
To a mixture of 3-(biphenyl-4-yloxymethyl)benzoic acid (2.36 g, 7.5 mmol, prepared as described in example 20) and 2 drops of N,N'-dimethylformamide in dry tetrahydrofuran (25 ml) was added dropwise thionyl chloride (1.7 ml, 22.5 mmol) and the resulting reaction mixture was stirred at reflux temperature for 3 h. The volatiles were evaporated in vacuo and the solid residue was dissolved in dichloromethane (20 ml) and added dropwise to a stirred suspension of 5-amino-tetrazole monohydrate (0.86 g, 8.3 mmol) and triethylamine (3.2 ml, 22.5 mmol) in dichloromethane (10 ml). After the addition was complete pyridine (5 ml) and 4-dimethylaminopyridine (10 mg) were added and the resulting mixture was stirred at room temperature for 48 h. The volatiles were evaporated in vacuo and the residue was suspended in water (100 ml) and acidified to pH=3 with concentrated hydrochloric acid. Ethyl acetate (100 ml) was added and the mixture was stirred for 0.5 h. The precipitate was filtered off and washed with water (2×10 ml) and dried in vacuo at 50° C. afforded 1.39 g (50%) of the title compound as a solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH2:8])=[N:4][CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=2)[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][C:20]1[CH:25]=[C:24]([C:2]2[S:6][C:5]([C:7]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)=[CH2:8])=[N:4][CH:3]=2)[CH:23]=[C:22]([NH:35][C:36]2[N:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[CH:39]=[CH:38][N:37]=2)[CH:21]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C=C(c1ccc(C(=O)OC)cc1)c1ncc(Br)s1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C=C(c1ccc(C(=O)OC)cc1)c1ncc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 29.8 %

Procedure:
A microwave vial was charged with methyl 4-[1-(5-bromo-1,3-thiazol-2-yl)-ethenyl]benzoate (INTERMEDIATE 89, 0.225 g, 0.694 mmol), N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 3, 0.263 g, 0.694 mmol), Pd2(dba)3 (0.032 g, 0.035 mmol), cesium carbonate (0.452 g, 1.388 mmol) and X-Phos (0.033 g, 0.069 mmol). The vial was sealed and purged with Argon gas. Dioxane (2.43 mL) and water (0.24 mL) were added and the mixture was stirred at 60° C. for 75 minutes. The temperature was increased to 90° C. and reacted overnight. The resulting solution was cooled and filtered through a celite plug, washing with EtOAc and then concentrated. Chromatography on silica gel (Biotage 100 G SNAP, 10-65% EtOAc/hexanes) afforded methyl 4-{1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethenyl}benzoate (103 mg, 0.207 mmol, 29.9% yield). MS ESI: [M+H]+ m/z 497.0.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:48]([C:49](=O)[CH3:50])=[C:47]([CH3:52])[O:46][N:45]=2)=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:48]([C:49]3[CH:50]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)=[C:47]([CH3:52])[O:46][N:45]=2)=[CH:40][CH:39]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2ccc(Cl)cc2)c1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 12 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-yl]-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (16 mg, 12% yield).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][N:11]([CH2:22][CH2:23][N:24]2C(=O)C3=CC=CC=C3C2=O)[C@@H:10]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:24][CH2:23][CH2:22][N:11]1[CH2:12][C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:10]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 3.1 %

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethyl-1-(2-phthal-imidoethyl)pyrrolidine (Compound 19) (0.64 g, 1.1mmol) was dissolved in ethanol (20 ml) and hydrazin, hydrate (0.215 ml, 4.4 mmol) was added. The clear solution was stirred for 4 hours at 40° C. and for 18 hours at room temperature. The white precipitate was filtered off and the filtrate evaporated in vacuo. The residue was partitioned between aqueous hydrochloric acid and methylene chloride. The water phase adjusted to pH 11with 2N sodium hydroxide and extracted with methylene chloride (2×100 ml) and with diethylether (100 ml). Drying of the combined organic phases with magnesium sulphate and evaporation of the solvent in vacuo afforded the crude product as an oil. Purification on silica gel (Eluent: Ethyl acetate) gave (2R,3R,4R)-1-(2-aminoethyl)-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (0.015 g) as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([O:29]C)=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B(Br)(Br)Br>ClC(Cl)C.ClCCl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([OH:29])=[CH:17][CH:18]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(Nc3cc(C)n[nH]3)nc(Sc3ccc(NC(C)=O)cc3)nc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(O)cc3n2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A solution of [2-(4-acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (23 mg, 5.54.10−5 mol) in dichloroethane (3 mL) is treated with 1M BBr3 in dichloromethane (222 μL, 2.21.10−4 mol). The mixture os heated at 80° C. for 4 hours before 1M BBr3 in DCM (222 μL, 2.21.10−4 mol) is added. The reaction mixture is heated at 80° C. for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench residual BBr3. The solvent is evaporated in vacuo and this operation repeated 3 times. 1M HCl (2 mL) is added to the solid residue and the suspension stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture water/EtOH (3/1, 8 mL). The mixture is neutralized with NaHCO3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and diethyl ether to give the desired [2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1>C(O)(=O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Reaction time: 5 h
Yield: 72.4 %

Procedure:
Crude 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole 8a (26 g) was dissolved in glacial acetic acid (330 ml) and PtO2 (0.7 g) was added. The mixture was hydrogenated in a Parr apparatus at 3 atm. for 5 hours. The catalyst was filtered off and excess acetic acid evaporated in vacuo. Water was added and pH was adjusted to >9 by addition of diluted aqueous NH4OH. Extraction with ethyl acetate (2×200 ml) and work-up of the combined organic phases yielded 19 g of crude title compound as a visceous oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2C(OC)=O)[O:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+].C1(P([N:38]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CO.O>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:38])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CCC)C1COc2cccc(N)c2C1
Reaction time: 4 h

Procedure:
3-Dipropylamino-5-methyloxycarbonylchroman (Example 2; 1.0 g, 3.4 mmol) was dissolved in methanol (20 ml). Sodium hydroxide (0.16 g, 4.1 mmol) in water (1.0 ml) was added and the solution was refluxed with nitrogen overnight. The solution was evaporated to dryness, toluene (20 ml) was added and again the solution was evaporated to dryness. The residue was dissolved in toluene 20 ml, diphenylphosphoryl azid (1.87 g, 6.8 mmol) was added and the solution was refluxed for 2 hours. Methanol (2.0 ml) was added and reflux was continued for 4 hours. The solution was cooled, washed with water and extracted with dilute HCl (aq.). The acidic water phase was neutralized NaOH (aq.) and extracted with toluene. The toluene-phase was dried with sodium sulphate and evaporated to dryness. The residue was dissolved in ethanol containing 10% NaOH (20 ml) and the solution was refluxed overnight. The solution was cooled and diluted with toluene. Washing with water, drying of the organic phase and evaporation to dryness afforded the title compound as an oil, which was converted to a dihydrochloride salt. Mp 173°-174° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10][C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][N:20]4[C:16](=[N:17][C:18]([C:24]5[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=5)=[CH:19]4)[C:15]=3[CH:31]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:33].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][N:20]4[CH:19]=[C:18]([C:24]5[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=5)[N:17]=[C:16]4[C:15]=3[CH:31]=2)=[O:33])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)C)CC3)ccc1OCC2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cccnc1-c1cn2c(n1)-c1cc(S(=O)C3CCN(C(C)C)CC3)ccc1OCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 9-(1-isopropylpiperidin-4-ylsulfanyl)-2-(3-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 7 (70 mg, 0.161 mmol) in DCM (10 mL) was added TFA (62 μL, 0.805 mmol) followed by a solution of m-CPBA (31 mg, 0.177 mmol) in DCM (2 mL). The resulting mixture was stirred for 15 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 5-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH affording 204 as a pale orange foam (65 mg, 90%). LCMS: RT1.92 min [M+H]+ 451.1. 1H NMR (DMSO, 400 MHz): δ 8.66 (1H, d, J=2.27 Hz), 8.40 (1H, dd, J=4.69, 1.63 Hz), 7.89 (1H, s), 7.64 (1H, ddd, J=7.65, 1.72, 0.84 Hz), 7.49 (1H, dd, J=8.50, 2.30 Hz), 7.23 (1H, d, J=8.72 Hz), 7.18 (1H, dd, J=7.96, 4.16 Hz), 4.60-4.53 (4H, m), 2.85-2.77 (2H, m), 2.73-2.59 (5H, m), 2.13-2.02 (2H, m), 1.76 (1H, bd, J=12.29 Hz), 1.58 (1H, bd, J=12.37 Hz), 1.52-1.38 (2H, m), 0.90 (6H, d, J=6.54 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1.[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1>>[CH2:19]([O:18][C:4]1[CH:3]=[C:2]([NH:1][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Br:26])=[CH:28][CH:29]=2)[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Product: O=C(OCc1ccccc1)c1ccc(NCc2ccc(Br)cc2)cc1OCc1ccccc1
Yield: 78 %

Procedure:
Primary aniline 1 was coupled to 4-bromobenzaldehyde on a 0.7 mmol scale via General Procedure A to furnish 2 (274 mg, 78%): δH (400 MHz, CDCl3) 4.12 (s, 2H, CH2, NHCH2Ph), 4.50 (br s, 1H, NH), 4.92 (s, 2H, CH2, CH2Ph), 5.18 (s, 2H, CH2, CH2Ph), 5.98 (d, J=1.8 Hz, 1H, CH (Ph)), 6.04 (dd, J=8.6 and 1.8 Hz, 1H, CH (Ph)), 7.02 (d, J=8.2 Hz, 2H, 2 CH (Ph)), 7.11-7.34 (m, 12H, 12 CH (Ph)), 7.70 (d, J=8.6 Hz, 1H, CH (Ph)); δC (100 MHz, CDCl3) 46.5, 65.4, 69.9, 97.0, 104.5, 108.2, 120.7, 126.4, 127.2, 127.4, 127.6, 128.0, 128.1, 128.4, 131.4, 133.9, 136.3, 137.0, 152.3, 160.4, 165.3; LRMS (ES+) calcd for [C28H24BrNO3+H] 502.10. found 502.06.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(F)c(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 65 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-fluoro-3-(trifluoromethyl)benzoic acid: MS (ESI): m/z 455 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>C1C=CC=CC=1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:2]([CH3:3])[CH3:1])=[CH:7][CH:6]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CNC
Solvent: c1ccccc1
Product: CN(C)Cc1ccc(Br)cc1

Procedure:
Reaction of dimethylamine with 4-bromobenzyl bromide in cold benzene gave 4-bromo-N,N-dimethylbenzylamine which was successively reacted with magnesium, formaldehyde, and cysteamine (in a similar procedure to Example 7) to give 2-[4-(dimethylaminomethyl)benzylthio]ethylamine as an oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:20]1[S:24][C:23]([NH2:25])=[N:22][N:21]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[S:24][C:23]([NH2:25])=[N:22][N:21]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: NCCCOc1cccc(CN2CCOCC2)c1
Reactant: Nc1nnc(Br)s1
Product: Nc1nnc(NCCCOc2cccc(CN3CCOCC3)c2)s1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-(4-morpholinylmethyl)phenoxy]1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([OH:16])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(OC([N:24]1[CH2:29][CH2:28][NH:27][C:26]([CH3:31])([CH3:30])[CH2:25]1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH3:30][C:26]1([CH3:31])[CH2:25][NH:24][CH2:29][CH2:28][N:27]1[C:14]([C:11]1[N:12]=[CH:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)[N:10]=1)=[O:16]
Reactant: Cc1ccc(-n2cnc(C(=O)O)n2)cc1F
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2cnc(C(=O)N3CCNCC3(C)C)n2)cc1F

Procedure:
This intermediate was prepared from 1-(3-fluoro-4-methyl-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]-triazol-3-yl)-methanone trifluoroacetate.