Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:27]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][C:31]=1[Cl:38])[CH3:28]>O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:35][CH2:34][C:33]1[CH:36]=[CH:37][C:30]([O:29][CH2:27][CH3:28])=[C:31]([Cl:38])[CH:32]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CCOc1ccc(CN)cc1Cl
Solvent: C1COCCO1
Product: CCOc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1Cl
Yield: 68.9 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.35 mmol) with 4-ethoxy-3-chloro-benzylamine (94.7 mg, 0.51 mmol) in anhydrous 1,4-dioxane (10 mL). Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (100:0 to 77:23 gradient) to obtain 7-chloro-6-(3-chloro-4-ethoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (111.3 mg, 68%). MS (ES+) m/z: 483 (M+Na)+.
Reaction SMILES: O[CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH2:6][O:5][CH2:4]1)=[CH:13][C:12]([O:17][CH2:18][CH3:19])=[C:11]([O:20][CH2:21][CH3:22])[CH:10]=3.S(Cl)([Cl:25])=O>C1C=CC=CC=1>[ClH:25].[Cl:25][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH2:6][O:5][CH2:4]1)=[CH:13][C:12]([O:17][CH2:18][CH3:19])=[C:11]([O:20][CH2:21][CH3:22])[CH:10]=3
Reactant: O=S(Cl)Cl
Reactant: CCOc1cc2c(cc1OCC)C1C(CO)COCN1CC2
Solvent: c1ccccc1
Product: CCOc1cc2c(cc1OCC)C1C(CCl)COCN1CC2
Product: Cl
Yield: 37 %

Procedure:
0.01 mole (3.08 g) of 1-(hydroxymethyl)-9,10-diethoxy-1,6,7,11b-tetrahydro-2H,4H-[1,3]oxazino[4,3-a]-isoquinoline is dissolved in 50 ml of absolute benzene. To the solution 0.05 mole (6 g) of sulfinyl dichloride is added dropwise, under ice cooling and stirring. Thereafter the reaction mixture is slightly refluxed for 3 hours. The excess of the solvent and sulfinyl dichloride is distilled off in vacuo. The residual brown oil is triturated with a small amount of ether to yield the desired compound in crystalline form in a yield of 37%.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[OH:6][C:7]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:17]O>>[CH3:17][O:10][C:9]([C:8]1[CH:12]=[C:13]([S:1]([OH:3])(=[O:5])=[O:2])[CH:14]=[C:15]([OH:16])[C:7]=1[OH:6])=[O:11]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: CO
Reactant: O=S(=O)(O)O
Product: COC(=O)c1cc(S(=O)(=O)O)cc(O)c1O

Procedure:
Concentrated sulphuric acid (4 ml) and 2,3-dihydroxybenzoic acid (1 g) were heated at 60° C. for 1 hour. Methanol (15 ml) was added and the solution stirred under reflux for a further 3 hours. The solvent was evaporated and the residue purified on Diaion HP 20 SS resin (aqueous methanol with 1% acetic acid) to give 3-methoxycarbonyl-4,5-dihydroxybenzene sulphonic acid (1.8 g); δ(DMSO-d6); 3.88(s,3H); 7.32(d,1H); 7.57(d,1H). This was treated as in F (above) (chromatography on silica with methanol/dichloromethane as eluent) to give the title compound as a crystalline solid; δ(CDCl3); 1.31(s,6H); 1.38(s,6H); 2.80-3.20(m,2H); 3.92(s,3H); 8.04(d,1H); 8.50(d,1H).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([F:39])[CH:32]=3)[N:11]([C:14]3[C:15](=[O:30])[N:16](CC4C=CC(OC)=CC=4)[CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:40][O:41][C:42]1[N:47]=[C:46]([O:48][CH3:49])[C:45](B(O)O)=[CH:44][N:43]=1.BrC1N(C(C)C)C2C(C3C=CC(C#N)=CC=3)N(C3C(=O)N(CC4C=CC(OC)=CC=4)C=C(Cl)C=3)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[Cl:20][C:18]1[CH:19]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:45]4[C:46]([O:48][CH3:49])=[N:47][C:42]([O:41][CH3:40])=[N:43][CH:44]=4)[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]=3[CH:10]2[C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([F:39])[CH:32]=2)[C:15](=[O:30])[NH:16][CH:17]=1
Reactant: COc1ccc(Cn2cc(Cl)cc(N3C(=O)c4cc(Br)n(C(C)C)c4C3c3ccc(C#N)c(F)c3)c2=O)cc1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(Cn2cc(Cl)cc(N3C(=O)c4cc(Br)n(C(C)C)c4C3c3ccc(C#N)cc3)c2=O)cc1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Solvent: ClCCl
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)c(F)c2)N(c2cc(Cl)c[nH]c2=O)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 125 but in the step corresponding to Step 125.1, 4-{2-bromo-5-[5-chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl}-2-fluoro-benzonitrile (Intermediate BE) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 4-{2-bromo-5-[5-chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl}-benzonitrile and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. Moreover, in this step, Pd(PPh3)4 was used instead of PdCl2(dppf).CH2Cl2 adduct. The title compound was obtained as a white solid. tR: 5.84 min (H PLC 2); ESI-MS: tR=0.94 min, [M+H]+ 549/551 (LC-MS 1); TLC: Rf=0.19 (EtOAc).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O-:18][C:19]#[N:20].[K+]>CO.O>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][C:19](=[O:18])[NH2:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(=O)ON(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred suspension of 10.70 g of N,N-dibenzylhydroxylamine in 25 ml of methanol is admixed dropwise with a solution of 4.53 ml conc. hydrochloric acid in 10 ml of water. A solution of 4.06 g of potassium cyanate in 15 ml of water is then added and the resulting suspension is stirred at room temperature for 3 hours. The crude product is removed by filtration and further purified by liquid chromatography to afford the title compound as a white solid; m.p. 127°-29° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:8]1[N:9]=[C:10]([C@@H:12]3[CH2:16][C@H:15]([CH3:17])[CH2:14][NH:13]3)[NH:11][C:7]=1[CH:6]=[CH:5]2.[CH3:21][O:22][C:23]([NH:25][C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:27](O)=[O:28])=[O:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:24])[NH:25][C@H:26]([C:27]([N:13]1[CH2:14][C@@H:15]([CH3:17])[CH2:16][C@H:12]1[C:10]1[NH:11][C:7]2[CH:6]=[CH:5][C:4]3[C:18](=[CH:19][CH:20]=[C:2]([Br:1])[CH:3]=3)[C:8]=2[N:9]=1)=[O:28])[CH:30]([CH3:32])[CH3:31]
Reactant: C[C@@H]1CN[C@H](c2nc3c(ccc4cc(Br)ccc43)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2c(ccc3cc(Br)ccc32)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.9 %

Procedure:
To a solution of 7-bromo-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-3H-naphtho[1,2-d]imidazole (1.05 g, 3.2 mmol; Preparation 12) in DCM (20 mL) was added (S)-2-Methoxycarbonylamino-3-methyl-butyric acid (672 mg, 3.84 mmol), DIPEA (825 mg, 6.4 mmol), and HATU (1.82 g, 4.8 mmol). The reaction mixture was stirred at RT for 4 h and extracted with DCM (3×250 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (1:1 EtOAc:petroleum ether) to provide the title intermediate (1.2 g) (m/z): [M+H]+ calcd for C23H27BrN4O3 487.13, 489.12 found 489.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+].C(O)(=O)C>CN(C=O)C.O>[NH:17]1[C:11]([C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])=[N:12][N:19]=[N:18]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1Sc1ccccc1N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1ccccc1Sc1ccccc1-c1nnn[nH]1
Reaction time: 5 h
Yield: 66.5 %

Procedure:
In 25 ml of DMF were suspended 2.4 g of 2-(2-aminophenylthio)benzonitrile (prepared in accordance with Reference Example 5, Step 4), 3.4 g of sodium azide and 1.7 g of ammonium chloride and the suspension was stirred at 110°-120° C. for 5 hours. After cooling, the reaction mixture was diluted with water, acidified with acetic acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated and the residue was crystallized from ethyl acetate and isopropyl ether to give 1.9 g of the title compound as white crystals, m.p. 153°-156° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3][CH:2]=1.[H-].[Na+].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O1CCCC1>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:8][CH2:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: OCc1cncnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2cncnc2)cc1
Reaction time: 0.08 h

Procedure:
Pyrimidin-5-ylmethanol (510 mg, 4.63 mmol) in tetrahydrofuran (8 mL) at room temperature was treated with sodium hydride (185 mg, 4.63 mmol) and stirred for 5 minutes. p-Toluenesulfonyl chloride (883 mg, 4.63 mmol) was added, and the resulting mixture stirred for one hour to form pyrimidin-5-ylmethyl 4-methylbenzenesulfonate. In a separate flask 3-methyloxindole (682 mg, 4.63 mmol) and N,N′-dimethylethylenediamine (1.538 mL, 10.19 mmol) in tetrahydrofuran (16 mL) were cooled to −78° C. and treated dropwise with n-butyllithium (2.5M in hexanes, 4.08 mL, 10.2 mmol). The mixture was allowed to warm to 0° C. and stirred for 15 minutes. The mixture was recooled to −78° C. To this mixture was added the tetrahydrofuran solution of pyrimidin-5-ylmethyl 4-methylbenzenesulfonate via cannula; the resulting reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. Water (50 mL) was added, and the mixture extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 25S, eluting with 0-100% ethyl acetate/hexane to afford 3-methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([Br:11])=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:5]=2[N:6]=1.N1C=CC=CC=1.[CH3:20][C:21]1[S:25][C:24]([C:26](Cl)=[O:27])=[CH:23][CH:22]=1>ClCCl>[Br:11][C:10]1[C:4]2[S:3][C:2]([NH:1][C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:27])=[N:6][C:5]=2[C:7]([O:12][CH3:13])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: COc1ccc(Br)c2sc(N)nc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Br)c2sc(NC(=O)c3ccc(C)s3)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Amino-7-bromo-4-methoxybenzothiazol (2.33 g, 9 mmol) is dissolved in dichloromethane (100 ml) and at 0° C. treated with pyridine (2.2 ml, 27 mmol) and 5-methyl-thiophene-2-carbonyl chloride (2.2 g, 13.5 mmol). The reaction mixture is allowed to warm to room temperature and after stirring for additional 18 h quenched with water (100 ml). After separation of the phases, the aqueous phases are extracted twice with ethyl acetate. The combined organic layers are then washed with brine, dried and avaporated to dryness. Flash chromatography on silica (eluent ethyl acetate/cyclohexane 1:1 to 4:1) and final recrystallization from ethyl acetate affords the product as off-white solid. (34 mg, 69%). MS: m/e=384 (M+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br.N.CO.C(Cl)(Cl)Cl>CC(O)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[C:16]([Br:18])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(c1)ncn2Cc1ccccc1
Reactant: BrBr
Agent: N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1ccc2c(ncn2Cc2ccccc2)c1Br
Yield: 60 %

Procedure:
To a solution of 1-benzyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 40 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitate. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CHCl3) to provide 0.90 g (2.5 mmol, 60%) of the product.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([CH3:14])=[N:9][C:10]([Br:13])=[CH:11][CH:12]=2)[C:3]1=[O:15].C1COCC1.[CH3:21][C:22]([O-:24])=[O:23].[K+]>C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>[C:22]([O:24][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([CH3:14])=[N:9][C:10]([Br:13])=[CH:11][CH:12]=2)[C:3]1=[O:15])(=[O:23])[CH3:21]
Reactant: Cc1nc(Br)ccc1N1CCC(Br)C1=O
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC1CCN(c2ccc(Br)nc2C)C1=O
Temperature: 70 °C
Yield: 51.3 %

Procedure:
A 500 mL round-bottom flask was charged with crude 3-bromo-1-(6-bromo-2-methylpyridin-3-yl)pyrrolidin-2-one from step A (18.5 g), THF (50 mL), 18-Crown-6 (576 mg, 2.18 mmol) and KOAc (12.84 g, 131 mmol). The mixture was heated at 70° C. under argon overnight. After cooling the reaction mixture to room temperature, ethyl acetate (50 mL) was added. The organic layer was separated and washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to a dark solid, which was purified by flash chromatography (silica gel, 20-100% ethyl acetate/hexane) to give 1-(6-bromo-2-methylpyridin-3-yl)-2-oxopyrrolidin-3-yl acetate (8.9 g, 65% yield for two steps) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.38 (q, J=8.3 Hz, 3H), 5.43 (t, J=8.2 Hz, 1H), 3.47-4.03 (m, 3H), 2.62-2.90 (m, 1H), 2.38-2.56 (m, 4H), 2.06-2.32 (m, 5H); MS (ESI) 314 (M+H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Br:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.CN([CH:25]=[O:26])C>C1COCC1>[Br:11][C:12]1[C:13]([CH:25]=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To isopropylmagnesium chloride lithium chloride complex solution (1.3M in THF; 50 mL, 65 mmol) was added 2,2,6,6-tetramethylpiperidine (11.5 mL, 68.3 mmol) dropwise, and the mixture was stirred overnight at room temperature. To 55 mL of the resulting solution at −25° C. under N2 was added 3-bromoquinoline (6.52 mL, 48 mmol) dropwise, and the reaction was stirred for 1 hour. DMF (3 mL) was added, and the reaction was slowly warmed to room temperature and monitored by analytical LCMS. The mixture was quenched with saturated aqueous NH4Cl and worked-up. The residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[I:25]I.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[C:30]([CH3:37])[CH:29]=1>ClCCl>[C:14]1([P:7](=[O:36])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][I:25])=[C:30]([CH3:37])[CH:29]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: II
Reactant: Cc1cc(Br)ccc1CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CCI
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL flask in an ice bath was added triphenyl phosphine (6.17 g, 22.8 mmol), imidazole (1.6 g, 22.8 mmol) and 100 mL of anhydrous dichloromethane. Once dissolved, iodine (5.79 g, 22.8 mmol) was added. The reaction was then stirred for about 30 minutes (ppt formed). The 2-(4-bromo-2-methylphenyl)ethanol (3.93 g, 18.3 mmol) was added in batches and the flask was rinsed with the remaining DCM (22 mL) which was also added to the reaction mixture. The reaction was warmed to room temperature and was stirred overnight. The reaction mixture was filtered through a small pad of celite and washed with DCM (100 mL). The filtrate was washed with saturated aqueous sodium thiosulfate (200 mL) and brine 200 mL. The organics were concentrated in vacuo to furnish a white solid (triphenyphosphine oxide+desired product). The material was triturated with heptanes for 5-10 mins then filtered to remove the majority of the triphenylphosphine oxide The filtrate was concentrated in vacuo to furnish a total of 5.86 g (98.8%) of the title compound as a clear oil that solidified upon standing. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.30 (s, 3H) 3.04-3.20 (m, 2H) 3.21-3.39 (m, 2H) 7.02 (d, J=8.20 Hz, 1H) 7.23-7.29 (m, 1H) 7.30-7.38 (m, 1H).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[C:4]([OH:8])(=[O:7])[CH:5]=[CH2:6].CCC>>[CH:4](=[O:7])[CH2:5][CH3:6].[C:4]([OH:8])(=[O:7])[CH2:5][CH3:6].[CH2:1]=[CH:2][CH3:3]
Reactant: C=CC(=O)O
Solvent: C=CC
Solvent: CCC
Product: CCC(=O)O
Product: CCC=O

Procedure:
When the reaction is a two-stage partial oxidation of propylene to acrylic acid, some or even all of the fresh propane may also be supplied into the starting reaction gas mixture for the second stage of the partial oxidation (however, this starting reaction gas mixture is sometimes not explosive even when this qualification was actually true for the starting reaction gas mixture for the first stage of the partial oxidation). This is advantageous in particular because the undesired side reaction of propane to give propionaldehyde and/or propionic acid starts in particular from the first partial oxidation stage (propylene→acrolein) under the conditions thereof. It is also advantageous to divide a fresh propane supply substantially uniformly between the first and the second partial oxidation stage.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:18]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21](O)[CH2:20][CH2:19]1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[N:15]([CH:21]1[C:22]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[O:18][CH2:19][CH2:20]1)=[N+:16]=[N-:17]
Reactant: OC1CCOc2ncccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC1CCOc2ncccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(Prep ref: Phompson, A. S. et. al. J. Org. Chem., 1993, 58, 5886-5888). Diphenyl phosphoryl azide (0.81 mL) was added to a suspension of 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol (0.37 g) in dry toluene (10 mL) then the mixture was cooled to 0° C. under an Ar atmosphere. Neat DBU (0.56 mL) was added and the resultant biphasic mixture was stirred at 0° C. for 2 hr and then at RT for 15 hr. The biphasic solution was diluted with sat. NaHCO3 and extracted with DCM (2×). The combined organics were concentrated and purified by silica gel chromatography using 10, 25 and 50% EtOAc/Hex elutants to afford the titled product (0.31 g) NMR CDCl3 1H δ 8.2 (dd, 1H), 7.6 (dd, 1H), 7.0 (dd, 1H), 4.7 (dd, 1H), 4.4 (m, 2H), 2.2 (m, 1H), 2.1 (m, 1H); MH+=177.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[C:6]=1[C:7](OCC)=O.[CH:20]1([C:23]([NH2:25])=O)[CH2:22][CH2:21]1.[P+2](Cl)(Cl)[Cl:27]>C(Cl)Cl>[Cl:27][C:7]1[C:6]2[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[CH:4][S:3][C:2]=2[N:1]=[C:23]([CH:20]2[CH2:22][CH2:21]2)[N:25]=1
Reactant: Cl[P+2](Cl)Cl
Reactant: NC(=O)C1CC1
Reactant: CCOC(=O)c1c(-c2ccccc2OC)csc1N
Solvent: ClCCl
Product: COc1ccccc1-c1csc2nc(C3CC3)nc(Cl)c12
Temperature: 100 °C
Yield: 44.6 %

Procedure:
Ethyl 2-amino-4-(2-methoxyphenyl)thiophene-3-carboxylate (1 g, 3.606 mmol), cyclopropanecarboxamide (0.3069 g, 3.606 mmol) and phosphorous (V) trichloride (0.6723 mL, 7.212 mmol) were combined and heated to 100° C. over the weekend in a Reactivial. The reaction mixture was diluted with DCM (25 mL), washed with water (2×25 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of petroleum ether to 50/50 petroleum ether/ethyl acetate to afford 4-chloro-2-cyclopropyl-5-(2-methoxyphenyl)thieno[2,3-d]pyrimidine (0.51 g). LCMS: purity 100%, RT=4.63 min, M+1=317.0
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CN(C)C=O.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[CH2:25]([O:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-hydroxy-3-methylbenzoate (25 g, 150.44 mmol, 1.00 equiv), N,N-dimethylformamide (250 mL) and Cs2CO3 (103 g, 316.13 mmol, 2.10 equiv). This was followed by the addition of (bromomethyl)benzene (31 g, 181.25 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 1.2 L of ethyl acetate. The resulting mixture was washed with 3×800 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 40 g (crude) of methyl 2-(benzyloxy)-3-methylbenzoate as brown oil. MS (ESI) m/z 257 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([CH2:12]O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>ClCCl>[ClH:16].[Cl:16][CH2:12][N:9]1[CH:10]=[CH:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8]1
Reactant: OCn1ccc(-c2ccccc2)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCn1ccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.74 g of 3-phenyl-1H-pyrazole-1-ylmethanol was dissolved to 50 ml of dichloromethane. 3.4 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. Hexane and chloroform was added to the residue to produce a crystal. The crystal was collected to obtain 2.01 g of 1-(chloromethyl)-3-phenyl-1H-pyrazole hydrochloride.