Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[N:34]1([CH2:40][C:41]2[CH:42]=[C:43]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][NH2:54])[CH:48]=3)[CH:44]=[CH:45][CH:46]=2)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:76])[C:66]1[CH:71]=[CH:70][C:69]([CH2:72][C:73](O)=[O:74])=[CH:68][CH:67]=1>C(Cl)(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:76][N:65]([CH3:64])[C:66]1[CH:71]=[CH:70][C:69]([CH2:72][C:73]([NH:54][CH2:53][C:49]2[CH:48]=[C:47]([C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([CH2:40][N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[CH:42]=3)[CH:52]=[CH:51][CH:50]=2)=[O:74])=[CH:68][CH:67]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: NCc1cccc(-c2cccc(CN3CCNCC3)c2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(CC(=O)NCc2cccc(-c3cccc(CN4CCNCC4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
A mixture of PyBOP (0.08 mmol in 200 mL of DMF), {[3′-(1-piperazinylmethyl)-3-biphenylyl]methyl}amine (44 mmol in 200 mL of DMF) and DIPEA (30 mL) were added to [4-(dimethylamino)phenyl]acetic acid (0.07 mmol). The resulting mixture was stirred for 16 hours at room temperature, then the solvent was removed under vacuum. The residue was dissolved in methanol and purified by loading onto a SPE cartridge (SCX, 500 mg), washing with MeOH, and eluting with a 2 M solution of NH3 in MeOH. The NH3 fraction was collected and evaporated under vacuum to give a gum which was dissolved in 1:1 CHCl3/TFA (0.5 mL). After stirring for 2 hours, the solvent was removed under vacuum and the residue was dissolved in MeOH. The free base of the compound was obtained by loading the solution onto a SPE cartridge (SCX, 500 mg), washing with MeOH, and eluting with 2M NH3/MeOH. The ammonia fraction was collected and the solvent was removed under vacuum to give the title compound (14.6 mg). LC/MS: m/z, 443 (M+H), 2.21 min.
Reaction SMILES: C1(C2(CO)CCCN2C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=CC=CC=1C(O)=O)([O-])=O.[OH:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O.[CH2:41]([O:43][C:44](=[O:49])/[CH:45]=[CH:46]/[CH:47]=[O:48])[CH3:42]>C1(C)C=CC=CC=1>[CH2:41]([O:43][C:44]([CH:45]1[C:46]([CH:47]=[O:48])=[CH:35][C:34]2[C:33](=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:32]1)=[O:49])[CH3:42]
Reactant: O=Cc1ccccc1O
Reactant: CCOC(=O)/C=C/C=O
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: OCC1(c2ccccc2)CCCN1c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1Oc2ccccc2C=C1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 29 %

Procedure:
To a stirred mixture of commercially available (S)-(−)-α{tilde over (α)}Diphenyl-2-pyrrolidinemethanol (0.83 g, 3.28 mmol) in toluene (40 mL) was added 2-nitrobenzoic acid (0.55 g, 3.28 mmol), commercially available 2-Hydroxybenzaldehyde (2.00 g, 16.38 mmol) and (E)-4-oxo-but-2-enoic acid ethyl ester (2.51 g, 19.65 mmol). After addition was complete the mixture was stirred at room temperature for 3 days. Upon completion of the reaction the toluene was removed by vacuum distillation. The residue was diluted with ethyl acetate and washed with water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The organic fraction was then dried over magnesium sulfate. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; (0% to 100% ethyl acetate/hexane) to afford 3-formyl-2H-chromene-2-carboxylic acid ethyl ester as a yellow oil, 1.09 g (29% yield). (Ref: Chem. Eur. Journal; 2007, 13, pg 574).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:25][C@H:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:25][C@H:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:27](=[O:28])[N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:15])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
A 10 mL round-bottomed flask was charged with 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.12 g, 0.36 mmol), (R)-2-amino-3,3-dimethyl-1-(pyrrolidin-1-yl)butan-1-one hydrochloride (137 mg, 0.53 mmol), HOBt (61 mg, 0.40 mmol) and EDC (76 mg, 0.40 mmol). Then added DMF (1.6 mL) followed by N,N-diisopropylethylamine (0.16 mL, 0.92 mmol). The light yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×50 mL). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 8 g SiO2 with EtOAc/hexanes (gradient: 0-60% EtOAc) to afford 195 mg of (R)-2-cyclopropyl-N-(3,3-dimethyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a viscous yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:21])[C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+:23].C(O)(=[O:26])C.O>ClC(Cl)C>[OH-:19].[Na+:23].[OH:26][CH2:2][CH2:3][N:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:21]
Reactant: CN(CCCl)C(=O)c1ccccc1C(=O)c1ccccc1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CN(CCO)Cc1ccccc1C(O)c1ccccc1
Product: [OH-]
Temperature: 86 °C

Procedure:
A solution of 144 kg. of N-(2-chloroethyl)-N-methyl-o-benzoylbenzamide (481 moles) in 378 kg. of dichloroethane was prepared. A mixture of 50 kg. of this solution, sodium borohydride (273 kg., 721.5 moles, 1.5 equivalents) and dichloroethane (120 liters) at 46° C., was treated with acetic acid (0.5 kg.). The temperature rose steadily to reflux at 86° C. The remaining dichloroethane solution was added slowly, the exotherm maintaining the mixture at reflux without applied heat during the addition and for two hours after addition was complete. Thin layer chromatographic analysis was used to check for the completeness of reaction (had the reaction been found to be incomplete, a small further addition of sodium borohydride could then have been made). The complex was then decomposed by cautious slow addition of 100 liters of water at the reflux temperature and then 50 liters of 40% (w/w) aqueous sodium hydroxide solution to form 2-[N-(2-hydroxyethyl)-N-methylaminomethyl]benzhydrol in dichloroethane. The benzhydrol in dichloroethane was water washed to pH 8 and subsequently cyclized to 5-methyl-1-phenyl-1,3,4,6-tetrahydro5H-benz(f)-2,5-oxazocine as follows:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([OH:19])[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:19][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCN1CCOCC1
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.8 %

Procedure:
To a solution of 0.72 g (2.49 mmol) of 3-amino-6-hydroxy-7-methoxy-naphthalene-2-carboxylic acid tert-butyl ester in 7.5 ml of tetrahydrofuran is added 0.46 mL (3.74 mmol) of 4-(2-hydroxyethyl)morpholine, followed by the addition of 1.34 g (4.98 mmol) of diphenyl-2-pyridylphosphine and 0.6 mL (3.87 mmol) of diethyl azadicarboxylate. The resulting mixture is stirred at room temperature for 1.5 hours, quenched with water, diluted with ethyl acetate and the two layers are separated. The organic layer is extracted with 0.2N hydrochloric acid. After neutralizing the aqueous layer with a saturated solution of sodium bicarbonate, it is extracted with ethyl acetate. The ethyl acetate extract is dried over anhydrous sodium sulfate, filtered and evaporated to yield a brown oil. The oil is purified by silica gel chromatography, utilizing a gradient of ethyl acetate/hexane (85:15 to 100:0), to give 0.7 g of 3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylic acid tert-butyl ester as an orange solid, mp 125-127° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH:54]1[CH2:57][NH:56][CH2:55]1>CN(C=O)C>[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH:54]1[CH2:57][N:56]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:55]1
Reactant: Clc1ccccc1OC1CNC1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CC(Oc2ccccc2Cl)C1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 26.7 %

Procedure:
DIPEA (141 mg, 1.09 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (67 mg, 0.27 mmol) in DMF (3 mL) followed by HOBt (39 mg, 0.28 mmol) and EDCI (56 mg, 0.28 mmol). After 2 minutes of stirring, 3-(2-chloro-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (60 mg, 0.27 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Partitioning with cold water and ethyl acetate and concentration of the organic layer after drying over sodium sulfate afforded a residue which was purified by column chromatography (using silica gel 60-120 and 100% EtOAc as eluent) to afford 30 mg (26.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[3-(2-chloro-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 411, 98.45%. 1H NMR (300 MHz, DMSO-d6): δ 8.34 (d, 1H), 8.28 (d, 1H), 8.12 (t, 1H), 7.72 (d, 1H), 7.44 (m, 3H), 7.38 (m, 1H), 7.26 (m, 1H), 6.8 (m, 1H), 6.7 (d, 1H), 5.1 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.8 (m, 3H).
Reaction SMILES: O.[OH:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[N:5]([CH3:15])[C:4]=1[C:16]1[NH:20][N:19]=[N:18][N:17]=1.[OH:21][C:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2S(=O)(=O)N(C)C=1C1NN=NN=1.C(Cl)(=O)C1C=CC=CC=1.Cl>N1C=CC=CC=1>[C:22]([O:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:13])(=[O:14])[N:5]([CH3:15])[C:4]=1[C:16]1[NH:20][N:19]=[N:18][N:17]=1)(=[O:21])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:26]=1
Reactant: CN1C(c2nnn[nH]2)=C(O)c2ccccc2S1(=O)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: CN1C(c2nnn[nH]2)=C(OC(=O)c2ccccc2)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-hydroxy-2-methyl-3-(tetrazol-5-yl)-1,2-benzothiazine 1,1-dioxide hemihydrate (2.88 g) in pyridine (10 ml) was added dropwise benzoyl chloride (1.02 ml) at 5°-10° C. After being stirred at room temperature for 1 hour, the mixture was poured into 0.6N HCl (200 ml) with vigorous stirring. The resulting solids were collected by filtration and washed with water. The solids were dissolved in dichloromethane (100 ml), washed with water and dried over sodium sulfate to give crude 4-benzoyloxy-2-methyl-3-(tetrazol-5-yl)-1,2-benzothiazine 1,1-dioxide, 4.24 g.
Reaction SMILES: [C:1]([O:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13](=[O:20])[NH:12][C:11]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1>[C:1]([O:9][C:10]1[C:11]([C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13]([O:20][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CO
Reactant: COC(=O)c1[nH]c(=O)c2cccnc2c1OC(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(OCC(=O)N(C)C)c2cccnc2c1OC(=O)c1ccccc1

Procedure:
To a cold (0° C.) suspension of methyl 8-(benzoyloxy)-5-oxo-5,6-dihydro[1,6]-naphthyridine-7-carboxylate (3.24 g, 10 mmol), 2-hydroxy-N,N-dimethylacetamide (1.13 g, 11 mmol), and triphenylphosphine (5.24 g, 20 mmol) in THF (100 mL), diethyl azodicarboxylate (3.1 mL, 19.6 mmol) was added over a period of 3 minutes. The resultant mixture was stirred at room temperature for two days. The product mixture was treated with 1 M aq HCl and extracted with methylene chloride. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residual oil was subject to column chromatography on silica gel eluting with 1-2% methanol in ethyl acetate. Collection and concentration of the appropriate fractions provided the slower eluting o-alkylated isomer as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH:14]([CH3:16])[CH3:15])[CH:4]=1.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19].C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH:14]([CH3:16])[CH3:15])[C:4]=1[Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(OC)cc1OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c([Si](C)(C)C)c1OC(C)C

Procedure:
More specifically, Scheme 3 shows compound of the formula 9 is prepared by adding a mixture methyl 4-methoxy-2-(l-methylethoxy)benzoate of the formula (10) and chlorotrimethylsilane to a -70° C. -78° C. tetrahydrofuran solution of lithium diisopropylamide to give methyl 4-methoxy-2-(1-methylethoxy)-3-(trimethylsilyl)benzoate (11) regioselectively.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([NH2:14])[C:8]2=[CH:7][N:6]=1.N1C=CC=[CH:22][CH:21]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>O1CCOCC1>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([NH:14][C:29]([CH:26]3[CH2:28][CH2:27][CH2:22][CH2:21]3)=[O:30])[C:8]2=[CH:7][N:6]=1
Reactant: c1ccncc1
Reactant: Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Reactant: O=C(Cl)C1CC1
Solvent: C1COCCO1
Product: O=C(Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12)C1CCCC1

Procedure:
To a solution of 6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-ylamine (45 mg, 0.17 mmol) in 1.7 mL of dioxane was added 14 uL pyridine and cyclopropane carbonyl chloride (21 uL, 0.17 mmol). The reaction mixture was heated to reflux for three hours, then cooled and chromatographed through silica (20%-50% EtOAc in hexanes) to afford 32 mg of cyclopentanecarboxylic acid [6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-amide, MP=206.3-207.51° C., MS (M+H)=360.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:19]=[CH:20][C:21]=1[Cl:22].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=4)[CH2:28][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(3,4-dichlorophenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 87% overall yield. FDMS m/e=419 (M+ of free base). α[D]589 =-7.76 (c=0.82, methanol).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]3[CH3:49])=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH2:14]1>O.C(OCC)(=O)C>[CH:13]1([O:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]3[CH3:49])=[CH:22][CH:23]=2)[CH2:14][CH2:15][CH2:16]1
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.45 g), sodium hydrogen carbonate (2.10 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(cyclobutyloxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.02 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.41 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.73 g, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:19]([CH2:18][CH2:17][CH2:16][Cl:15])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1ccc(Br)cc1
Reaction time: 4 h
Yield: 76.8 %

Procedure:
4-Bromoaniline (0.86 g, 5.0 mmol) was dissolved in CH2Cl2 (15 mL), pyridine (0.5 mL) was added, and 3-chloropropanesulfonyl chloride (0.6 mL, 5.0 mmol) was added. The mixture was stirred for 4 hours, diluted with ethyl acetate, and then washed with water, 2N HCl, brine, dried over MgSO4, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 5-60% ethyl acetate in hexane) to afford 1.2 g (77%) N-(4-bromophenyl)-3-chloropropane-1-sulfonamide.
Reaction SMILES: Cl[Si:2]([CH3:18])([CH3:17])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:15])=[C:4]1[CH3:16].CC[N:21]([CH2:24][CH3:25])CC.C(N)(C)(C)C.[CH3:31][CH2:32][CH2:33][CH2:34]CC>>[CH:24]1([NH:21][Si:2]([CH3:18])([CH3:17])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([CH3:15])=[C:4]2[CH3:16])[CH2:25][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCCCCC
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2cc3c(cc21)CCC3
Reactant: CCN(CC)CC
Solvent: CC(C)(C)N
Product: CC1=C(C)C([Si](C)(C)NC2CCCCC2)c2cc3c(cc21)CCC3
Reaction time: 16 h
Yield: 90.9 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2,3-dimethyl-s-indacen-1-yl)silane (5.00 g, 0.01806 moles) was stirred in hexane (80 mL) as NEt3 (3.29 g, 0.03251 moles) and t-butylamine (1.81 g, 0.01824 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.55 g, 90.9 percent).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:6]=1.[Li+].[OH-].Cl>C1COCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH:8]=[CH:9][C:5]([CH2:4][C:3]([OH:17])=[O:2])=[CH:6]2)=[CH:11][CH:12]=1
Reactant: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccn(-c2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester (100 mg, 0.43 mmol) in THF (1 mL) at 0° C. was added dropwise 2N aqueous LiOH (0.5 mL). Afer warming to ambient temperature over 4 hours, the mixture was added dropwise to 0.5N aqueous HCl (10 mL). The resultant light brown solid was collected by filtration, washed with H2O, and dried in vacuo over P2O5 to yield 700 mg (74%) of analytically pure 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid as a solid, mp 100-2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29]C(=O)OC(C)(C)C)=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:46][CH:47]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(N)nc3)n2)cc1
Yield: 95.2 %

Procedure:
A solution of tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.145 g, 0.228 mmol) and TFA (Aldrich) (1.0 mL, 13 mmol) in DCM (3 mL) was stirred at rt for 1 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (40 mL) and DCM (20 mL). The aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×40 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (25 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-10%) to give N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)pyridine-2,5-diamine (0.116 g, 95%) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 11.51 (s, 1H); 8.80 (dd, J=7.67, 1.53 Hz, 1H); 8.18-8.33 (m, 1H); 8.12 (d, J=1.75 Hz, 1H); 7.78 (dd, J=8.70, 2.27 Hz, 1H); 7.19 (t, J=8.84 Hz, 4H); 6.85 (t, J=8.84 Hz, 4H); 6.70 (dd, J=7.67, 4.75 Hz, 1H); 6.50 (d, J=8.77 Hz, 1H); 4.83 (d, J=6.58 Hz, 4H); 4.26 (br. s., 2H); 3.69-3.91 (m, 6H); 2.56 (s, 3H). m/z (ESI, +ve ion) 535.1 (M+H)+.