Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15](Cl)=[O:16].[CH3:23][C:24]1[CH:32]=[C:28]([C:29]([OH:31])=[O:30])[C:27]([NH2:33])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15]([NH:33][C:27]1[C:28](=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=1)[C:29]([OH:31])=[O:30])=[O:16]
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=CC(=O)Nc2ccc(C)cc2C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
In a mixture of 3 g of 5-methylanthranilic acid in 30 ml of chloroform is dissolved 3 ml of triethylamine, to this mixture is added a solution of 4.2 g of 3,4-dimethoxycinnamoylchloride in chloroform under cooling. The mixture is stirred at room temperature for 2 hours and then heated under reflux for 2 hours. The reaction mixture is concentrated under a reduced pressure, to the residue is added water and hydrochloric acid is added to make the mixture the weakly acidic. The precipitated crystals are collected by filtration recrystallized from ethanol to obtain 4.8 g of N-(3,4-dimethoxycinnamoyl)-5-methylanthranilic acid as pale yellow needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.[CH2:15]([C:17]1[O:21][C:20]([NH2:22])=[N:19][N:18]=1)[CH3:16].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]([NH:22][C:20]1[O:21][C:17]([CH2:15][CH3:16])=[N:18][N:19]=1)=[O:14]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: CCc1nnc(N)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nnc(NC(=O)c2ccc(S(C)(=O)=O)cc2Cl)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
415 mg (1.77 mmol) of 2-chloro-4-(methylsulfonyl)benzenecarboxylic acid and 200 mg (1.77 mmol) of 5-ethyl-1,3,4-oxadiazol-2-amine are dissolved at RT in 9 ml of CH2Cl2. Then 1.68 g (2.64 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added, the mixture is stirred at RT for one hour and then 0.246 ml (1.77 mmol) of triethylamine, 43 mg (0.35 mmol) of 4-dimethylaminopyridine are added. The reaction mixture is stirred at RT for 48 h and then washed twice with 4 ml each time of water, and purified by column chromatography (prep. HPLC; acetonitrile/water). Yield 41 mg (6%).
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:4]1=[O:33])=[CH:22][CH:21]=[CH:20][CH:19]=3.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[ClH:1].[C:34]([O:2][C@@H:3]1[C@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:4]1=[O:33])=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Agent: Cl
Product: CCN(CC)CCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Yield: 93 %

Procedure:
A mixture of 2.5 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(diethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one hydrochloride and 25 mL of acetic anhydride was stirred and heated at 100° for 17 hours. The excess of reagent was removed under reduced pressure and the residue was crystallized from ethyl acetate to give 2.5 g (93%) of (±)-cis-3-(acetyloxy)-5-[2-(diethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one hydrochloride, mp 211°-212°.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:32]=[CH:31][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[C:35]1[CH:36]=[C:37]([NH:42][C:43]([CH:45]2[CH2:47][CH2:46]2)=[O:44])[CH:38]=[CH:39][C:40]=1[CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:45]1([C:43]([NH:42][C:37]2[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]4[CH:31]=[CH:32][C:9]([CH2:8][N:5]5[CH2:6][CH2:7][S:2](=[O:1])(=[O:33])[CH2:3][CH2:4]5)=[CH:10][CH:11]=4)=[CH:17][CH:18]=3)[CH:36]=2)=[O:44])[CH2:46][CH2:47]1
Reactant: CC1(C)OB(c2ccc(NC(=O)c3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)OC1(C)C
Reactant: Cc1ccc(NC(=O)C2CC2)cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2CC2)cc1-c1ccc(NC(=O)c2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Yield: 7.8 %

Procedure:
A mixture of 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl) -N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (70 mg), cyclopropanecarboxylic acid (3-bromo-4-methyl-phenyl)-amide (38 mg) in DME (4 ml) and water (1.5 ml) containing cesium carbonate (50 mg) and tetrakis(triphenylphosphine) palladium (0) (10 mg) was heated to reflux for 18 h. The cooled mixture was then partitioned between water and ethyl acetate. The dried extracts were evaporated and the residue purified on silica gel. Elution with 0-30% DCM:EtOH:NH3; 20:8:1 in DCM gave the title compound as a tan solid (6 mg)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1CS(N)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:8][S:25]([CH3:28])(=[O:27])=[O:26])[CH:39]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 43.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorophenethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.148 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfon amide (Intermediate 17) (58 mg, 0.178 mmol) using sodium carbonate (47 mg, 0.444 mmol) and Pd(PPh3)2Cl2 (5 mg, 0.0074 mmol) in DME/water (10/1 ml). This afforded 27 mg (43.8% yield) after purification by column (Silica gel 60/120) using 30% ethyl acetate in hexane as eluent.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=O.O.[OH-].[NH4+:29]>CO>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:5]([C:3]([NH2:29])=[O:2])[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: COC(=O)C1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C(C(N)=O)CCC2c2ccc(F)cc2)cc1

Procedure:
A solution of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (1.3 g, 3.44 mmol) in MeOH (75 ml) and ammonium hydroxide solution (50 ml, 25%) was stirred at room temperature for 72 h. The volume of the solution was reduced to 50 ml and water (150 ml) was added. The title compound precipitated as a white solid (0.95 g, yield 76%), m.p. 137° C. and MS: m/e=363.1 (M+H+).
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.ClC(Cl)C.[C:26]1([C:32]#[C:33][P:34](=[O:48])([O:38][C:39]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH2:40])[O:35][CH2:36][CH3:37])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Au]>[CH2:36]([O:35][P:34]1(=[O:48])[CH:33]=[C:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:40]=[C:39]([CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:38]1)[CH3:37]
Reactant: C=C(Cc1ccccc1)OP(=O)(C#Cc1ccccc1)OCC
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccccc2)C=C(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
Method 1—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tent-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl 3-phenylprop-1en-2-yl phenylethynylphosphonate (example 3, 98 mg, 0.3 mmol) was put thereinto, and when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-phenyl-6-benzyl-1,2-oxaphosphorin 2-oxide (84.1 mg, 86%) which is a title compound.
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]2[C:37]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[C:38]([C:43]#[N:44])[C:39]([C:40](O)=[O:41])=[C:33]2[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]2[C:37]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[C:38]([C:43]#[N:44])[C:39]([C:40](=[O:41])[NH2:3])=[C:33]2[CH2:32]1)=[O:30])([CH3:26])([CH3:25])[CH3:27]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(c(C(=O)O)c(C#N)c2-c2ccccc2)C1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(c(C(N)=O)c(C#N)c2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
A stirred solution of triethylamine (3.34 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.30 g) and 1-hydroxybenzotriazole hydrate (1.62 g) in dry dimethylformamide (120 mL) was treated with 7-cyano-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2,8-dicarboxylic acid 2-tert-butyl ester (4.40 g, Reference Example 19). After stirring at room temperature for a further 15 minutes the reaction mixture was treated with ammonium chloride (1.28 g) and then heated at 80° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and then evaporated. The residue was treated with water and ethyl acetate. The organic phase was separated, washed with a 1M aqueous solution of sodium hydroxide (20 mL) and then water (20 mL). The organic phase was then dried over magnesium sulfate and evaporated to give a brown gum. The gum was triturated with diethyl ether to give the title compound (3.80 g) as a white solid, m.p. 214–215° C. 1H NMR [(CD3)2SO]: δ 7.59–7.50 (m, 5H), 7.41–7.27 (bs, 1H), 7.08–6.93 (bs, 1H), 4.75 (s, 2H), 3.92 (t, 2H), 3.62 (t, 2H) and 1.40 (s, 9H).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[F:19][C:20]([F:44])([F:43])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24].C(#N)C>O>[F:19][C:20]([F:43])([F:44])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41][N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][C:1]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]
Reactant: c1ccc(-c2ccc(N3CCNCC3)cc2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(-c4ccccc4)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
A solution of 0.4 g (1.678 mmol) of 1-biphenyl-4-yl-piperazine, 0.682 g (1.6 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 0.223 ml (1.6 mmol) of triethylaminein 20 ml acetonitrile is stirred for 14 hours at 60° C. and then diluted with water. It is extracted with ethyl acetate and the organic phase is dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/ethanol=40:1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>>[CH3:32][CH:31]([CH3:33])[C:30]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)=[O:34]
Reactant: CC(C)C(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Product: CC(C)C(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
2-Methyl-1-((R)-3-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidin-1-yl)-propan-1-one was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and isobutyryl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]=[N:18][N:17]=[C:16]1[CH3:20].[CH2:22]=[O:23]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:16]([CH3:20])=[N:17][N:18]=[C:19]1[CH2:22][OH:23]
Reactant: C=O
Reactant: Cc1nncn1-c1ccccc1C(=O)c1ccccc1Cl
Solvent: Cc1ccccc1C
Product: Cc1nnc(CO)n1-c1ccccc1C(=O)c1ccccc1Cl
Temperature: 122 °C

Procedure:
In the manner given in Example 4, 2'-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone, paraformaldehyde and xylene are warmed under nitrogen to about 122° C. to give 2'-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:10][CH2:11][Cl:12]>>[Cl:12][CH2:11][CH2:10][N:6]1[CH2:7][CH2:8][CH:3]([F:2])[CH2:4][CH2:5]1
Reactant: FC1CCNCC1
Reactant: ClCCBr
Agent: Cl
Product: FC1CCN(CCCl)CC1
Yield: 21.1 %

Procedure:
The title compound has been prepared according to the similar manner described in 86-B (i) using 4-fluoropiperidine hydrochloride (1.00 g, 7.16 mmol) and 1-bromo-2-chloroethane (717 μL, 8.60 mmol). The crude product has been purified by silica gel column chromatography (EtOAc/hexane=10/90→40/60) to obtain pure title compound (250 mg, 21%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13].[H][H]>[Pd].C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: Nc1c(CCO)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCO)c1N

Procedure:
A suspension of 10% palladium on carbon (66 mg) and 2-(2-amino-3-nitrophenyl)ethanol [See Seno, Kaoru; Hagishita, Sanji; Sato, Tomohiro; Kuriyama, Kaoru; J. Chem. Soc. Perkin Trans. 1; 2012 (1984) for the synthesis of this reagent] (531.5 mg, 2.92 mmol) in absolute ethanol (50 mL) was shaken under 40 psi hydrogen for 3 hours. After filtration and concentration, crude 2-(2,3-diaminophenyl)ethanol (474.4 mg) was obtained as a red oil, which crystallized on standing: Rf=0.08 (75% ethyl acetate in hexanes); 1H NMR (DMSO-d6) δ2.58 (t, 2H, J=6.9 Hz), 3.53 (t, 2H, J=7.2 Hz), 4.32 (br s, 5H), 6.29 (m, 2H), 6.40 (dd, 1H, J=6.9, 2.1 Hz).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:17])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:19]([CH3:18])(=[O:21])=[O:20])=[C:12]([CH3:17])[CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(N)c(C)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2ccc(NS(C)(=O)=O)c(C)c2)CC1

Procedure:
1-Acetyl-4-(4-amino-3-methylphenyl)piperazine (7.89 g) was dissolved in pyridine (130 ml). Methanesulphonyl chloride (7.9 ml) was added dropwise with stirring. The mixture was reduced in volume after 2 hours by evaporation and then stirred overnight. The resulting slurry was partitioned between water (125 ml) and dichloromethane (100 ml), and the aqueous layer was further extracted with dichloromethane (2×100 ml), 5% methanol in dichloromethane (2×100 ml), and ethyl acetate (2×125 ml). The combined organic layers were dried (sodium sulphate) and evaporated, and the residue was chromatographed in 5% methanol in dichloromethane over t.l.c. grade silica, the product-containing fractions, after evaporation, yielding a foam (5.93 g), Rf 0.29 (5% methanol/dichloromethane/silica), used directly in step (D). A small sample from a second run was recrystallized from ethyl acetate/hexane, m.p. 153°-4°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH:32]1([N:38]=[C:39]=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][C:39]([NH:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:40])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: O=C=NC1CCCCC1
Product: Cc1cc(F)ccc1-c1nc(NCCNC(=O)NC2CCCCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 78.1 %

Procedure:
The title compound from Example 157 (42.3 mg, 0.0001 mol) was treated with cyclohexylisocyanate (12.5 mg, 0.00011 mol) in the same manner as described in Example 158. Purification afforded 43 mg (78%) of the title compound as a red solid (m.p. 178°-183°) LC MS (m/e)=551 (MH+). Rt=2.38 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].[Br:14]Br>>[Br:14][CH:3]([CH:2]([CH3:13])[CH3:1])[C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: Cc1ccncc1C(=O)CC(C)C
Reactant: BrBr
Product: Cc1ccncc1C(=O)C(Br)C(C)C
Yield: 85.9 %

Procedure:
By the reaction in the same manner as in Example 53-ii) using 3-methyl-1-(4-methylpyridin-3-yl)butan-1-one (3.10 g) and bromine (2.68 g), the title compound (3.69 g) was obtained as a pale-yellow powder.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:13]=[C:14]([CH3:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].N1CCCCC1.CC(O)=O>C1C=CC=CC=1>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:15]([C:14](=[O:13])[CH3:20])[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc2c(c1)CCCO2
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccc2c(c1)CCCO2)C(C)=O
Yield: 60.47 %

Procedure:
A solution of 6-iodochroman (13.8 g, 53.1 mmol) in tetrahydrofuran (THF) (143 mL) was cooled to −78° C. in a dry ice/acetone bath and then treated with n-BuLi, 2.5M solution in hexanes (23.35 mL, 58.4 mmol). The mixture was stirred for 10 minutes before being treated with N,N-dimethylformamide (6.16 mL, 80 mmol) and the resultant was warmed to ambient temperature and stirred for 10 minutes. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the crude chroman-6-carbaldehyde as a yellow solid which was used without further purification. LC/MS (m/z) ES+=163.22 (M+1). A solution of the crude chroman-6-carbaldehyde, methyl 3-oxobutanoate, piperidine (0.263 mL, 2.66 mmol) and AcOH (0.152 mL, 2.66 mmol) in Benzene (113 mL) was refluxed (DS-trap) overnight. The mixture was concentrated and diluted with ethyl acetate. The dilution was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-30% hexanes/ethyl acetate) the afford methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate (mixture of E and Z isomers, 8.352 g, 32.08 mmol, 60.47% yield) as a thick yellow oil. 1H NMR (400 MHz, CHLOROFORM-d, major isomer) δ ppm 7.48 (s, 1 H), 7.22-7.12 (m, 2 H), 6.78 (d, J=8.6 Hz, 1 H), 4.27-4.18 (m, 2 H), 3.92-3.81 (m, 3 H), 2.77 (t, J=6.3 Hz, 2 H), 2.39 (s, 3 H), 2.06-1.99 (m, 2 H); 1H NMR (400 MHz, CHLOROFORM-d, minor isomer) δ ppm 7.58 (s, 1 H), 7.16-7.08 (m, 2 H), 6.79-6.71 (m, 1 H), 4.23-4.18 (m, 2 H), 3.84-3.78 (m, 3 H), 2.76 (t, J=6.4 Hz, 2 H), 2.38 (s, 3 H), 2.03-1.96 (m, 2 H); LC/MS (m/z) ES+=261.2 (M+1).
Reaction SMILES: [C:1]1([O:7]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=O.C(O[CH2:17][CH2:18][CH2:19]C)=O.C=CCCCCCC.C(O)#CCCCCC(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:17][CH2:18][CH3:19]
Reactant: COc1ccccc1
Reactant: CCCCOC=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)CCCCC#CO
Solvent: C=CCCCCCC
Solvent: O
Product: CCCCCCCCCO
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 500 mL autoclave was charged with 0.76 mmol palladium (II)acetate, 1.07 mmol of a mixture of 1.2-bis(9-phosphabicyclononyl)ethane, 20.2 mL of anisole (as solvent), 0.45 mL methanesulfonic acid (MSA), 4.80 mL water, 7.91 mL butyl formate (as promoter), and 156 mL octene, 83 ml isononynol. The autoclave was flushed with an equimolar mixture of carbon monoxide and hydrogen pressurized to a total pressure of 50 bar. The autoclave was then sealed and the mixture was heated to 110° C. The reaction was continued for 8 hours and subsequently the reaction mixture was cooled to room temperature and the pressure released. 163 g of nonyl alcohol product was produced (94% conversion of starting material). The reaction rate was about 0.36 hr-1. There was no noticeable paraffin make. This example illustrates that the use of a formic acid derivative as a promoter results in high conversion/high selectivity reactions with excellent reaction rates.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14]OC2=O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[BrH:17].C(O)(=O)C>CCOCC.CO>[BrH:17].[Br:17][CH2:14][CH2:15][NH:11][CH2:10][CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=C1OCCN1CCn1ccnc1[N+](=O)[O-]
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1nccn1CCNCCBr
Reaction time: 18 h

Procedure:
To 3.5 g (15 mmol) of 3-[2-(2-nitro-1H-imidazol-1-yl)ethyl-2-oxazolidinone was added 30 ml of 31% HBr/acetic acid and the mixture was stirred for 18 hours at 20°-25° C. The mixture was diluted with ether and methanol and the resulting solid was collected. Recrystallization from ethanol/water gave 3.0 g of the desired product, N-(2-bromoethyl)-2-nitro-1H-imidazole-1-ethanamine, monohydrobromide (54%): mp 103°-104° C.