Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:21]1([CH:27]2[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[OH:33][C:30]1([C:2]2[C:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:28][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)Nc1ncccc1Br
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To a solution of tert-butyl (3-bromopyridin-2-yl)carbamate (4 g) in THF (dry) (20 mL) was added dropwise n-butyllithium (1.6 M in hexane) (20.1 mL) at −78° C. and the mixture was stirred at the same temperature under nitrogen for 1 hr to give a yellow suspension. A solution of 4-phenylcyclohexanone (3.06 g) in THF (dry) (30 mL) was added dropwise at −78° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. and extracted with EtOAc. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (560 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1/[CH:18]=[CH:19]/[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.[CH3:42][Sn:43](Cl)([CH3:45])[CH3:44].[NH4+].[Cl-]>C1COCC1>[CH2:25]([C:24]1[CH:23]=[C:22]([Sn:43]([CH3:45])([CH3:44])[CH3:42])[S:21][C:20]=1/[CH:19]=[CH:18]/[C:14]1[S:15][C:16]([Sn:43]([CH3:45])([CH3:44])[CH3:42])=[CH:17][C:13]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCc1ccsc1/C=C/c1sccc1CCCCCCCCCCCC
Reactant: C[Sn](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc([Sn](C)(C)C)sc1/C=C/c1sc([Sn](C)(C)C)cc1CCCCCCCCCCCC
Temperature: -78 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
(E)-1,2-Bis(3-dodecylthienyl)ethylene (12) (10.4 mmol, 2.00 g) was dissolved in anhydrous THF (43.2 mL) and cooled to −78° C. under nitrogen. n-Butyllithium (21.84 mmol, 13.7 mL) was then added dropwise. The resulting solution was warmed to room temperature over 30 min and stirred at that temperature for 3 h. The mixture was then cooled to −78° C. before trimethyltin chloride (21.84 mmol, 4.35 g) in anhydrous THF (26 mL) was added dropwise. After addition, the mixture was warmed to room temperature over 4 h and stirred for additional 20 h at room temperature. The reaction mixture was poured into saturated NH4Cl solution (100 mL) and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude solid was recrystallized from ethanol to give desired product 13 in 73% yield. 1H-NMR (CDCl3, 400 MHz) ppm 0.36 (s, 18H) ppm 0.88 (t, 6H, J=6.9 Hz) ppm 1.30 (m, 36H) ppm 1.59 (td, 4H, J=7.3 Hz, J=14.9 Hz) ppm 2.65 (m, 4H) ppm 6.94 (s, 2H) ppm 7.00 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:10]=2[C:11]#[N:12])[CH:7]=1.[OH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[OH:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([C:13]4[CH:18]=[CH:17][C:16]([O:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:15][CH:14]=4)[C:10]=3[C:11]#[N:12])[CH:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(Br)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(-c3cccc(O)c3)cnc12
Temperature: 65 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To a solution of 6-bromo-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (782 mg, 2.0 mmol) in dioxane (10 mL) and H2O (10 mL) was added 3-hydroxyphenylboronic acid (276 mg, 2.0 mmol), Pd(PPh3)4 (240 mg, 0.2 mmol) and Na2CO3 (424 mg, 4.0 mmol). After stirring at 65° C. under N2 for 16 hr, the mixture was concentrated and 100 mL of DCM, 10 mL of CH3OH, 100 mL of H2O were added. Organic layers were separated from aqueous layers and dried over Na2SO4 and purified by chromatography column on silica gel eluting with DCM/CH3OH to afford 500 mg (62%) of 6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl) pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI) m/e [M+1]+ 404.9.
Reaction SMILES: OC1C=CC=C(O)C=1[C:9]1[C:10]2[NH:14][C:13]([C:15](C3C(O)=CC=CC=3O)=[C:16]3[N:48]=[C:19]([C:20](C4C(O)=CC=CC=4O)=[C:21]4[NH:39][C:24](=[C:25](C5C(O)=CC=CC=5O)[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2.C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:10]12[CH:9]=[C:29]3[N:30]=[C:26]([CH:27]=[CH:28]3)[CH:25]=[C:24]3[NH:39][C:21]([CH:22]=[CH:23]3)=[CH:20][C:19]3=[N:48][C:16]([CH:17]=[CH:18]3)=[CH:15][C:13]([NH:14]1)=[CH:12][CH:11]=2
Reactant: Oc1cccc(O)c1-c1c2nc(c(-c3c(O)cccc3O)c3ccc([nH]3)c(-c3c(O)cccc3O)c3nc(c(-c4c(O)cccc4O)c4ccc1[nH]4)C=C3)C=C2
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
On the other hand, a solution of 5,10,15,20-tetra(2',6'-dihydroxyphenyl)porphyrin in dry tetrahydrofuran is refluxed at the boiling point in an atmosphere of nitrogen, pivalic anhydride (40 times of the molar quantity) is added and then a small quantity of 4-dimethylaminopyridine is added. The mixture is refluxed for 10-24 hours. The reaction mixture is extracted by a suitable organic solvent (such as dichloromethane, chloroform, ether or the like), and the resulting solution is washed with dilute hydrochloric acid and with water. The organic layer is collected and the solvent is distilled away under reduced pressure. The residue obtained is purified by, for example, silica gel chromatography to obtain a porphyrin having no metal M (in the above process, the compound represented by H2T2,6 -dipivPP).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:9]([NH:17]C(=O)OC(C)(C)C)[CH2:10][NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:6]=[CH:7][CH:8]=1.[ClH:27]>ClCCl.O1CCOCC1>[ClH:27].[NH2:17][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:25])[F:26])[CH:4]=1)[CH2:10][NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15]
Reactant: CCOC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)NCC(N)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of 527 mg (1.40 mmol) of the compound from Example 103A in 9.6 ml of dichloromethane was admixed at RT with 9.4 ml (37 mmol) of 4M hydrogen chloride in dioxane and stirred for 1 h. Then all of the volatile constituents were removed on a rotary evaporator. Drying of the residue in an HV gave 437 mg (94% of theory) of the title compound.
Reaction SMILES: [NH:1]1[CH:8]=CC(N)=[N:4][C:2]1=[O:3].FF.[F:11][C:12](F)(F)[CH2:13][OH:14]>>[F:11][C:12]1[C:13](=[O:14])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: OCC(F)(F)F
Agent: FF
Product: O=c1[nH]cc(F)c(=O)[nH]1

Procedure:
The reaction and the treatment were carried out in the same manner as in Example 1 but using a solution of cytosine (1.11 g) in 2,2,2-trifluoroetanol (100 ml) and blowing the fluorine gas therein at 20° C. to give 5-fluorouracil (0.72 g). Yield, 55%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C-]#N.[Na+].[N:25]12CCN(CC1)C[CH2:26]2.O>CS(C)=O>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:26]#[N:25])[N:7]=1
Reactant: C1CN2CCN1CC2
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(Cl)n1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Temperature: 75 °C
Reaction time: 21 h
Yield: 861.5 %

Procedure:
(2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-iodo-benzyl)-amine (10.0 g, 24.0 mmoles) and sodium cyanide (5.6 g, 0.12 moles) are dissolved in 40 ml of DMSO and 1,4-diaza bicyclo[2,2,2]octane (0.27 g, 2.4 mmoles) is added at rt. The mixture is stirred at 75° C. for 21 h. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 8.4 g of desired 4-[(2,2-dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile in 86% yield.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:26])[NH:15][CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:48]2[C@H:49]([CH3:72])[C@H:50]3[C@@H:67]([C@H:68]([OH:70])[CH3:69])[C:66](=[O:71])[N:51]3[C:52]=2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[Si:19]([O:18][CH2:17][CH2:16][NH:15][C:14]([C:12]1[N:13]=[C:9]([N:7]2[CH2:6][CH:5]([S:4][C:48]3[C@H:49]([CH3:72])[C@@H:50]4[C@@H:67]([C@H:68]([OH:70])[CH3:69])[C:66](=[O:71])[N:51]4[C:52]=3[C:53]([O:55][CH2:56][C:57]3[CH:58]=[CH:59][C:60]([N+:63]([O-:65])=[O:64])=[CH:61][CH:62]=3)=[O:54])[CH2:8]2)[S:10][CH:11]=1)=[O:26])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 3-acetylthio-1-{4-[2-(t-butyidimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (398.2 mg, 0.96 mmol) (obtained as described in Reference Example 33) in dimethylformamide (20 ml) was added hydrazine acetate (110 mg, 1.19 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (561.4 mg, 0.94 mmol) in acetonitrile (38 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.7 ml, 4.02 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene: acetonitrile (2:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (605.3 mg, yield 80%) as a pale yellow syrup.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1([CH2:18][CH2:19]Cl)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>O>[CH2:21]([N:28]1[CH2:19][CH2:18][C:4]2([C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:11][C:10]3[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:3][CH2:2]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: ClCCC1(CCCl)c2ccccc2Sc2ccccc21
Agent: Cl
Solvent: O
Product: c1ccc(CN2CCC3(CC2)c2ccccc2Sc2ccccc23)cc1

Procedure:
A mixture of 9,9-bis(2'-chloroethyl)thioxanthene (3.4 g.) and benzylamine (10 ml.) is heated under reflux for 2 hours, cooled diluted with water (100 ml.) and acidified with concentrated hydrochloric acid. The liquid is decanted from the residual gum which is triturated with water (200 ml.) when it solidifies. The solid is crystallised from ethanol to give 1'-benzylthioxanthene-9-spiro-4'-piperidine, m.p. 248° C. Addition of ether to the ethanolic filtrate remaining after removal, by filtration, of the base, yields 1' -benzylthioxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 263°-266° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[N:4]=[CH:5][N:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.17) (178 mg, 0.5 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a brown solid (112 mg, 41%). MS (ISN) 545.0 [(M−H)−]; mp 247° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10]2)[CH3:3]>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]2)[CH3:1]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 103.8 %

Procedure:
Ethyl 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.87 g) was dissolved in a mixture of tetrahydrofuran (20 mL) and ethanol (20 mL), and 1M aqueous sodium hydroxide solution (9 mL) was added to the mixture. After stirring at 60° C. for 1 h, the mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was cooled to 0° C. and 1M hydrochloric acid (10 mL) was added. The resulting white suspension was filtered to collect a white precipitate. The precipitate was dissolved in ethyl acetate and the solution was dried over magnesium sulfate, filtered, and concentrated to give the title compound (1.81 g, 100%) as a white amorphous solid. MS 390 (MH+).
Reaction SMILES: C(Cl)CCl.Cl.[NH2:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:9][C:8]=1[C:18]([OH:21])([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.[CH3:32][NH:33][CH2:34][C:35]1[N:36]([CH3:44])[C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[NH2:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:33]([CH3:32])[CH2:34][C:35]2[N:36]([CH3:44])[C:37]3[C:42]([CH:43]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:17])=[CH:9][C:8]=1[C:18]([OH:21])([CH3:20])[CH3:19]
Reactant: CNCc1cc2ccccc2n1C
Reactant: CC(C)(O)c1cc(/C=C/C(=O)O)cnc1N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc(N)c(C(C)(C)O)c1
Temperature: 35 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
EDC (0.13 g, 0.70 mmol) was added to a suspension of (E)-3-[6-Amino-5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-acrylic acid hydrochloride (0.15 g, 0.58 mmol), HOBt (0.09 g, 0.64 mmol), Methyl-(1-methyl-1H-indol-2-ylmethyl)-amine (0.11 g, 0.64 mmol) and (i-Pr)2EtN (0.49 mL, 2.9 mmol) in DMF (8 mL). The mixture was allowed to stir overnight at 35° C. The mixture was cooled to 0° C. and diluted with H2O (60 mL) with rapid stirring. The resulting precipitate was filtered, washed with H2O (20 mL) then dried under high vacuum. The solid was then triturated with Et2O, and the resultant white solid was collected, to yield 36 mg of product. An extraction on the original filtrate was done using EtOAc (2×75 mL) and the combined organic layers were washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. The resulting off-white solid was subjected to flash chromatography on silica gel using 10% methanol:dichloromethane. Yield: 138 mg (79.5%); 1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.68 (s, 1H), 7.52-7.40 (m, 3H), 7.15-6.98 (m, 3H), 6.58 (s, 2H), 6.41 and 6.25 (2×s, 1H), 5.49 (s, 1H), 5.04 and 4.85 (2×s, 2H), 3.69 (s, 3H), 3.10 and 2.98 (2×s, 3H), 1.53 (s, 6H); ESI MS m/z 379 [C22H26N4O2+H]+
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CN(C2CC2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1-Cyclopropylpiperazine (268, 1.76 g, 14.0 mmol) was dissolved in 15 mL DMF. To it were added 1-fluoro-4-nitrobenzene (1.00 g, 7.0 mmol) and DIEA (1.24 mL, 7.0 mmol). The mixture was stirred at 90° C. for overnight, cooled to RT, diluted with EtOAc, washed with water ×2, dried, concentrated in vacuo, subjected to silica flash column using 0 to 40% EtOAc in DCM to isolate 1-cyclopropyl-4-(4-nitrophenyl)piperazine (269). It was dissolved in 2:1 EtOAc/MeOH (80 mL/40 mL), and to it were added 40 μL 6N HCl and 10% Pd/C (0.5 g). The mixture was stirred at RT for overnight under a hydrogen balloon. It was filtered through celite, concentrated in vacuo to dryness to afford 4-(4-cyclopropylpiperazin-1-yl)aniline hydrochloride (270, 1.30 g, 73% overall) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9]C)=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COc1cc(CC(=O)O)c(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)Cc1cc(O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of (2-bromo-4-fluoro-5-methoxy-phenyl)-acetic acid (6.2 g, 23.5 mmol) in dichloromethane (100 ml) was added 1.0 M borontribromide in dichloromathane (94 ml, 94 mml). The mixture was stirred at room temperature for one hour. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromathane. The combined organic extract was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification by flash chromatography gave (2-bromo-4-fluoro-5-hydroxy-phenyl)-acetic acid (5.2 g, 89%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=4)=[O:18])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17](=[O:18])[NH:16][C:13]2[CH:14]=[CH:15][C:10]([N:7]3[C:6]4[CH:31]=[CH:32][C:3]([NH:2][C:33](=[O:35])[CH3:34])=[CH:4][C:5]=4[N:9]=[CH:8]3)=[CH:11][CH:12]=2)=[CH:21][C:22]=1[C:27]([F:29])([F:30])[F:28]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: CC(=O)Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-[5-aminobenzimidazol-1-yl]phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and acetic anhydride by the same method as in Example 41.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26](S(C)(=O)=O)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.N1(C(N)=O)CCNCC1.[CH:43]1([C:46]([OH:48])=O)[CH2:45][CH2:44]1>>[CH:43]1([C:46]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)=[O:11])=[CH:20][CH:19]=4)=[O:22])[CH2:24][CH2:25]2)=[O:48])[CH2:45][CH2:44]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: O=C(O)C1CC1
Agent: Cl
Agent: NC(=O)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)C5CC5)CC4)cc3c2)CC1
Yield: 89 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b), and cyclopropylcarboxylic acid 1-piperazineamide hydrochloride to afford the desired product as a light-brown foam (89%). MS (ISP): 452.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][O:13]C(C)(C)[N:11]2C(OC(C)(C)C)=O)[CH:5]=[C:6]([S:8][CH3:9])[CH:7]=1>Cl.O1CCOCC1>[NH2:11][C@@H:10]([C:4]1[CH:5]=[C:6]([S:8][CH3:9])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:14][OH:13]
Reactant: CSc1cc(F)cc([C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CSc1cc(F)cc([C@H](N)CO)c1
Temperature: 80 °C
Yield: 100 %

Procedure:
A solution of (S)-tert-butyl 4-(3-fluoro-5-(methylthio)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (278 mg, 0.814 mmol) in 4 M HCl in dioxane (2.4 mL) was heated to 80° C. overnight. There was still some starting material left. More 4 M HCl in dioxane (2.035 mL, 8.14 mmol) was added, and heated at 80° C. for another 10 h. Solvent was removed under reduced vacuum to provide (S)-2-amino-2-(3-fluoro-5-(methylthio)phenyl)ethanol (194 mg, 0.814 mmol, 100%). LCMS (m/z): 170.1 (MH+-56), 0.26 min.