Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:23])[CH:19]=[C:20](Cl)[CH3:21])[CH3:16]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:23])/[CH:19]=[C:20](/[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Br:7])[CH:9]=1)\[CH3:21])[CH3:16]
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(Br)c1
Temperature: 23 °C
Yield: 38.8 %

Procedure:
Potassium t-butoxide (10.5 g, 0.094 mol) was added to a stirred solution of 3-bromo-phenol (8.18 g, 0.047 mol) in tetrahydrofuran (30 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 7.00 g, 0.047 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-bromo-phenoxy)-but-2-enoic acid ethyl ester (5.20 g, 39%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][N:15]([CH3:29])[C:16]([C:18]1[C:19]2[CH2:20][CH2:21][NH:22][CH:23]([CH3:28])[C:24]=2[CH:25]=[CH:26][CH:27]=1)=[O:17]>>[CH3:14][N:15]([CH3:29])[C:16]([C:18]1[C:19]2[CH2:20][CH2:21][N:22]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:23]([CH3:28])[C:24]=2[CH:25]=[CH:26][CH:27]=1)=[O:17]
Reactant: CC1NCCc2c(C(=O)N(C)C)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(C(=O)N(C)C)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid dimethylamide to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2](=O)[CH3:3].[NH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]2[N:14]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:15][C:16]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:8]=12.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[Cl:13][C:12]1[C:7]([CH2:6][NH:5][CH:2]([CH3:3])[CH3:1])=[C:8]2[C:16]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:15][N:14]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[C:9]2=[CH:10][CH:11]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4CN)c21
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)NCc1c(Cl)ccc2c1C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)CC2
Reaction time: 8 h
Yield: 60.3 %

Procedure:
2-Propanone (12 mg, 0.20 mmol) was added to a solution of (R)-tert-butyl 4-(aminomethyl)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 0.041 mmol) in DCE (2 mL). The reaction was allowed to stir at room temperature for 15 minutes, at which point Na(OAc)3BH was added. The reaction was allowed to stir overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and concentrated. The residue was purified by column chromatography (15:1, DCM:MeOH) to give (R)-tert-butyl 5-chloro-4-((isopropylamino)methyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (13 mg, 58%) as an oil. LCMS (APCI+) m/z 526/528 [M+H]+; Rt=4.72 min. This material was taken up into DCM (2 mL), and 2N HCl in ether was added (1 mL). The reaction was allowed to stir for 1 hour, at which point it was concentrated to give (R)—N-4-((5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride salt (13 mg, 59%) as a solid. 1H NMR (D2O, 400 MHz) δ 8.52 (s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.51-4.38 (m, 4H), 4.15 (d, J=9.6 Hz, 1H), 3.71-3.5 (m, 5H), 3.16-2.96 (m, 5H), 2.46-2.18 (m, 3H), 2.06-2.00 (m, 1H), 1.89-1.74 (m, 2H), 1.34-1.32 (m, 6H). LCMS (APCI+) m/z 426/428 [M+H]+; Rt=2.38 min.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Br:5][C:6]1[CH:7]=[N:8][C:9](Cl)=[N:10][CH:11]=1.C(N(CC)CC)C>C(O)C>[Br:5][C:6]1[CH:7]=[N:8][C:9]([NH:3][CH2:2][CH2:1][NH2:4])=[N:10][CH:11]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NCCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: NCCNc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethane-1,2-diamine (200 mg) was added to a solution of 5-bromo-2-chloro-pyrimidine (500 mg) and triethylamine (1 mL) in ethanol (10 mL) at 0° C. The reaction mixture was stirred under nitrogen at room temperature overnight. The formed mixture was concentrated to give crude N1-(5-bromopyrimidin-2-yl)ethane-1,2-diamine. Yield: 687 mg (100% of theory).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[C:14]([F:13])([F:24])[F:25]
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccccc1C(F)(F)F
Yield: 61.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-(trifluoromethyl)benzoyl chloride (80 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 63 mg of N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)-2-(trifluoromethyl)benzamide as a brown oil (Yield: 61%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][OH:12])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:13]([O:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][O:12][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][C@H:16]([O:15][CH2:13][CH3:14])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:28][CH:27]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C/c1cc(Br)cc(Br)c1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(Br)cc(Br)c2)cc1)OCC
Yield: 76.1 %

Procedure:
The title compound (780 mg, 78%) was prepared from (E)-3-(3,5-dibromophenyl)-prop-2-en-1-ol (584 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
EX-1A) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (50 g, 0.24 mol) and N-bromosuccinimide (42.75 g, 0.24 mol) in 100 mL of carbon tetaachloride under nitrogen was added 2,2′-azobisisobutyronitrile (0.71 g, 0.004 mol). The resultant mixture was refluxed for 2 h, then cooled to room temperature and quenched with 300 mL of water. The organic layer was collected, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 66.0 g (96%) of the desired crude 3-(1,1,2,2-tetrafluoroethoxy)bromomethylbenzene product as a yellow oil. 1H NMR indicates that this oil is a mixture of products: 7% dibrominated, 67% monobrominated, and 20% starting material. The crude product was used without further purification. ESMS m/z=287 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CS(C)=O.Cl.[NH2:38][OH:39]>C(N(CC)CC)C>[OH:39][NH:38][C:29](=[NH:30])[CH2:28][CH:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:4][CH:5]=4)=[CH:11][CH:12]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: NO
Reactant: N#CCC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N=C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)NO
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of (4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetonitrile (0.15 g, 0.34 mmol, 1.0 equiv) in 4 Ml DMSO was added hydroxylamine hydrochloride (0.12 g, 1.7 mmol, 5.0 equiv) and triethylamine (0.25 Ml, 1.8 mmol, 5.2 equiv). The yellow solution was heated to 120° C. using microwave heating for 10 min. Additional portions of hydroxylamine hydrochloride and triethylamine were added, and the reaction was allowed to stir overnight at 75° C. The reaction was partitioned between EtOAc and water, and the organic extracts were washed with saturated NaHCO3 followed by brine. The organic layer was then dried over sodium sulphate, filtered, and concentrated in vacuo to afford the title compound which was used without further purification: (M+H)+ 471.2.
Reaction SMILES: [CH2:1]([C@:8]1([C:21](=[O:23])[NH2:22])[C:14]([CH3:16])([CH3:15])[S@@:13](=[O:17])[C@H:12]2[N:9]1[C:10](=[O:20])[C:11]2(Br)[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>O>[CH2:1]([C@:8]1([C:21](=[O:23])[NH2:22])[C:14]([CH3:16])([CH3:15])[S@:13](=[O:17])[C@H:12]2[N:9]1[C:10](=[O:20])[C@@H:11]2[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[S@@](=O)[C@H]2N(C(=O)C2(Br)Br)[C@@]1(Cc1ccccc1)C(N)=O
Solvent: O
Solvent: ClCCl
Product: CC1(C)[S@](=O)[C@@H]2[C@@H](Br)C(=O)N2[C@@]1(Cc1ccccc1)C(N)=O
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a cold (0° C.) solution of (2S,4R,5R)-2-benzyl-carbamoyl-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-4-oxide (1160 mg, 2.5 mmole) in dry methylene chloride (30 ml) triphenyl phosphine (837 mg, 5 mmole) was added and it was stirred for 15 minutes. The reaction mixture was treated with water and the layers were separated. The organic layer was washed with water, then with a saturated sodium hydrogen carbonate solution and again with water. The evaporation of dry (Na2SO4) organic layer under reduced pressure gave a foamy residue, which after chromatography on silica gel gave (2S,4S,5R,6S)-2-benzyl-carbamoyl-6-bromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-4-oxide (780 mg, 81.0%). Crystallization from diethyl ether gave the product as a white crystalline powder.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:19][CH3:20])[C:11]=1[C:21]#[N:22]>C(O)(=O)C>[Br:1][C:15]1[CH:14]=[C:13]([N+:16]([O-:18])=[O:17])[C:12]([NH:19][CH3:20])=[C:11]([C:21]#[N:22])[C:10]=1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3]
Reactant: BrBr
Reactant: CNc1c([N+](=O)[O-])ccc(-c2ccccc2Cl)c1C#N
Solvent: CC(=O)O
Product: CNc1c([N+](=O)[O-])cc(Br)c(-c2ccccc2Cl)c1C#N
Temperature: 86 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Bromine (0.54 mL, 10.43 mmol) was added slowly to a solution of Example 8A (2.0 g, 6.96 mmol) in acetic acid (20 mL) at r.t. The reaction was heated to 86° C. and stirred for 1 h. The cooled solution was quenched with sat. bisulfite solution and extracted with EtOAc. Organics were dried (MgSO4) and concentrated in vacuo to give 2.4 g (94%) of the title compound as an orange solid. 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 8.50 (br s, 1H), 7.40-7.55 (m, 3H), 7.18-7.26 (m, 1H), 3.46 (d, 3H, J=4.8 Hz). MS (ES) [m+H] calc'd for C14H9N3O2BrCl, 366, 368, 370; found 366, 368, 370.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>CS(C)=O>[O:21]=[C:15]1[C:14]2[CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]3)[CH:11]=[CH:10]4)[NH:20][C:19]=2[CH2:18][CH2:17][NH:16]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 231.7 %

Procedure:
A solution of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50 mg, 0.168 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (Small Molecules, Inc., Hoboken, N.J.; 168 mg, 0.840 mmol) in DMSO (0.5 mL) was stirred under argon at 100° C. for 19 h, then 130° C. for 5 h, then 150° C. for 17 h. The mixture was cooled to 25° C. and partitioned between DCM (30 mL) and water (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×20 mL). The combined organic extracts were sequentially washed with water (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude (R)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)amino)piperidine-1-carboxylate (179.7 mg) as a brown foam (used without further purification in the subsequent transformation): m/z (ESI, +ve) 462.4 (M+H)+.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([CH3:25])[NH:9][C:8]=1[CH3:26])=[O:6])[CH3:3].[CH2:27]([O:29][C:30](=[O:35])[C:31](Br)([CH3:33])[CH3:32])[CH3:28]>O>[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:31]([C:30]([O:29][CH2:27][CH3:28])=[O:35])([CH3:33])[CH3:32])=[CH:17][CH:18]=2)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([CH3:25])[NH:9][C:8]=1[CH3:26])=[O:6])[CH3:3]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na]
Solvent: O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(OC(C)(C)C(=O)OCC)cc1
Reaction time: 8 h

Procedure:
A solution of 2.3 g of sodium in 120 ml of alcohol is treated with 34.5 g of 2,6-dimethyl-4-(4-hydroxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and with 21.5 g of α-bromo-isobutyric acid ethyl ester added from a dropping funnel. The mixture is boiled overnight, added to water and extracted with ether. White crystals of melting point 215°C (benzene) are obtained from the evaporation residue.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([Cl:10])[C:6]([Cl:9])=[N:7][CH:8]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].O>CN(C=O)C>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:2][N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])[CH:8]=[N:7][C:6]=1[Cl:9]
Reactant: Clc1cc(CBr)cnc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromomethyl-2,3-dichloro-pyridine from step (a) above (121 mg, 0.5 mmol) and potassium phthalimide (139 mg, 0.75 mmol, Aldrich) in DMF (1 mL) was stirred at room temperature for 30 min. Water (5 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was suspended in 20% EtOAc/hexane, and filtered. The solid was washed with 20% EtOAc/hexane and dried in vacuo to give the title compound. MS (ESI, pos. ion) m/z: 307 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)C.Cl.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1>C(O)CCC.C(OC)(C)(C)C>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:31]=[CH:32][C:33]([N:36]2[C:4](=[O:3])[C:6]3=[C:7]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=4)[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]3=[N:37]2)=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nc2ccccc2c1Cl
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: COC(=O)c1ccc(-n2nc3c4ccccc4[nH]c(-c4ccc([N+](=O)[O-])cc4)c-3c2=O)cc1
Yield: 76.6 %

Procedure:
4-Chloro-2-(4-nitrophenyl)-quinoline-3-carboxylic acid ethyl ester (2.86 g, 0.008 mol) and 4-hydrazino-benzoic acid methyl ester hydrochloride (1.7 g, 0.008 mol) were stirred in n-butanol (70 mL) at 120° C. for 24 h. The bright orange suspension was diluted with tert-butylmethyl ether, filtered, washed with cold heptane and left to dry under suction to yield 4-[4-(4-nitrophenyl)-3-oxo-3,5-dihydropyrazolo[4,3-c]quinolin-2-yl]-benzoic acid methyl ester (2.7 g, 76%) as an orange solid, LCMS m/z 441.35 [M+H]+ @ RT 1.66 min: 84% purity.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[CH:9]=2)=[CH:6][N:7]=1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:37]([C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)=[O:38])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2nc(-c3cccc(CN)c3)cnc2N)C1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(-c2cccc(CNC(=O)c3ccc(F)cc3)c2)nc1C(=O)N[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
1,1-dimethylethyl (3S)-3-[({3-amino-6-[3-(amino-methyl)phenyl]pyrazin-2-yl}carbonyl)amino]piperidine-1-carboxylate (150.0 mg, 0.35 mmol) and 4-fluorobenzoic acid (50.0 mg, 0.36 mmol) was dissolved in DMF (5 mL) followed by the addition of HOBT (95.5 mg, 0.70 mmol) and EDCI (135.4 mg, 0.70 mmol). It was stirred at room temperature overnight. The reaction mixture was poured into water (20 mL), and extracted with ethyl acetate (2×30 mL) then dried over anhydrous sodium sulfate and filteration, concentration and purified by column chromatography (50% Ethylacetae/hexanes) and subsequently it was treated with 4.0 M HCl in dioxane (20 mL) to give compound 3-Amino-6-[3-({[(4-fluorophenyl)carbonyl]amino}methyl)phenyl]-N-[(3S)-piperidin-3-yl]pyrazine-2-carboxamide: 70.0 mg (46.6% yield). 1H NMR (400 MHz, d4-MeOH): δ 8.62 (s, 1H), 8.16 (s, 1H), 7.98 (m, 3H), 7.48 (m, 2H), 7.20 (m, 3H), 4.67(s, 2H), 4.38 (m, 1H), 3.45 (m, 1H), 3.38 (m, 1H), 3.18 (m, 1H), 3.00 (m, 1H), 2.18 (m, 2H), 1.80 (m, 2H); MS (EI) for C24H25N6O2F: 449.32 (MH+).
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[C:24]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][CH:30]=2)[CH:23]=[C:22]([C:34](O)=[O:35])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.[NH2:54][CH:55]([CH3:58])[CH2:56][OH:57]>C(Cl)Cl>[OH:57][CH2:56][CH:55]([NH:54][C:34]([C:22]1[CH:21]=[C:20]([C:14]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[F:12])[CH:25]=[C:24]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][CH:30]=2)[CH:23]=1)=[O:35])[CH3:58]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccnn3C(C)C)c2)c(F)c1
Reactant: CC(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NC(C)CO)cc(-c3ccnn3C(C)C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
EDCI (54.0 mg, 0.282 mmol) was added in one portion to a solution of 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (77.4 mg, 0.229 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.000 mmol) in CH2Cl2 (5 mL) at 0° C. After the reaction stirred at the same temperature for 1 hour, 2-amino-propan-1-ol (54 mg, 0.72 mmol) was added. The mixture was allowed to warm to room temperature and was stirred overnight. Solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 2′-Fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide as white solid (54 mg, 46%). MS (N+H)=396.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:25]1[CH2:30][CH:29]=[C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:27][CH2:26]1>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][N:25]1[CH2:26][CH:27]=[C:28]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[CH2:29][CH2:30]1)[CH2:22][CH2:21]2
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4ccccc34)CC1)CC2
Temperature: 80 °C
Yield: 67.8 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.348 g, 1.00 mmol) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.793 g, 4.00 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) followed by recrystallization from ethanol provided 0.254 g (68%, 40% ee) of 3-(1-{[(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a yellow crystalline powder. [α]D25=−28.22 (c 9.92 in chloroform, 40% ee); Rf=0.34 (silica, ethyl acetate:hexanes 4:1); mp 190-194° C. dec; Anal. Calcd. for C24H26N2O2.0.1 H2O: C, 76.61; H, 7.02; N, 7.44. Found: C, 76.42; H, 6.99 N, 7.43.
Reaction SMILES: CS(O[C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[C:9]([OH:11])(=[O:10])[CH:8]([C:7]1[CH:6]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:12]
Reactant: [H][H]
Reactant: CC(C(=O)O)c1ccccc1OS(C)(=O)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C(=O)O)c1ccccc1
Yield: 90 %

Procedure:
To a solution of 24.5 g. of 2-methane-sulphonyloxyhydratropic acid in 200 ml. of methanol 28 ml. of triethylamine and 2 g. of a 5% palladium-on-charcoal catalyst are added. The mixture is hydrogenated at 25° C., under atmospheric pressure until a calculated amount of hydrogen is used up. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and acidified with a 20% aqueous hydrochloric acid solution. The separated hydratropic acid is extracted with chloroform. The chloroform solution is dried over sodium sulphate, evaporated and the residue is distilled off. 13.5 g. (90%) of hydratropic acid are obtained, boiling at 145° C. (13 mmHg.); nD25 =1.5219.