Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:7]1[CH:11]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9][C@H:8]1[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=O)C=C.O.CCCC[SnH](CCCC)CCCC>C(Cl)Cl.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>[Si:19]([O:18][CH2:17][C@@H:8]1[CH2:9][C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:11][NH:7]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21]
Reactant: C=CCOC(=O)N1C=C(CC(=O)OC)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC1=CN[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C

Procedure:
A catalytic amount of PdCl2(PPh3)2 (84 mg, 0.12 mmol) was added to a stirred solution of the allyl carbamate 17 (1.10 g, 2.98 mmol) and H2O (0.32 mL, 17.8 mmol) in CH2Cl2 (36 mL) After 5 minutes stirring at room temperature, Bu3SnH (0.89 mL, 0.96 g, 3.30 mmol) was added rapidly in one portion. A slightly exothermic reaction with vigorous gas evolution immediately ensued. The mixture was stirred for 16 hours at room temperature under nitrogen at which time TLC (50% EtOAc/Petroleum Ether) revealed the formation of amine along with the complete consumption of starting material. After diluting with CH2Cl2 (30 mL), the organic solution was dried (MgSO4), filtered and evaporated in vacuo to give an orange oil which was purified by flash chromatography (50% EtOAc/Petroleum Ether) to afford the enamine 18 as a slightly orange oil (0.57 g, 67%): 1H NMR (270 MHz, CDCl3) δ7.53 and 7.48 (br s×2, 1H, NCH═CCH2CO2CH3), 4.35-4.13 (m, 1H, NCHCH2OTBDMS), 3.82-3.17 (m, 7H, NCH═CCH2CO2CH3, NCHCH2OTBDMS and CO2CH3), 2.64-2.04 (m, 2H, NCH═CCH2CO2CH3CH2), 0.90-0.88 (m, 9SiC(CH3)3), 0.09-0.00 (m, 6H, Si(CH3)2); MS (EI), m/z (relative intensity) 285 (M+., 1), 270 (M—CH3, 7), 254 (6), 242 (4), 230 (6), 228 (M—tBu, 100), 212 (4), 196 (3), 168 (13), 115 (3), 89 (10), 80 (4), 73 (13); MS (CI), m/z (relative intensity) 342 (M+.57, 7), 302 (M+. +17, 7), 286 (M+. +1, 100), 228 (M—tBu, 100).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:42]3[CH2:43][CH2:44][CH2:45][CH:40]([CH2:39][OH:38])[CH2:41]3)=[O:36])[C:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OCC1CCCNC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCCC(CO)C1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-hydroxymethyl-piperidine (Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C34H42N5O3Cl2 [(M+H)+] 638.2659, observed 638.266.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2Cl)[CH3:3].[CH3:22][N:23]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24]1.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:26]1[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=1)[CH3:3]
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: Cn1cc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: C[C@H](N)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a mixture of (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (1) (1.0 g, 3.35 mmol) and 1-methyl-1 h-pyrazole-4-boronic acid (815 mg, 5.02 mmol) in anhydrous DMA (10 mL) in a sealed tube, PdCl2(dppf) (219 mg, 0.27 mmol) and aqueous Na2CO3 solution (1 M, 10.0 mL, 10.0 mmol) were added and the resulting mixture was stirred at 120° C. for 3 h. The reaction mixture was allowed to cool to RT, quenched with water, and then extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-8% MeOH-DCM) to afford the product, (S)-3-(1-aminoethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (63) (990 mg, 85% yield) as a pink/magenta solid. ESI-MS m/z: 345.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[BH4-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:17]([CH2:18][OH:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [BH4-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester (1.0 g, 3.61 mmol) in THF (20 mL) is stirred at RT for 10 min. HATU (1.51 g, 3.97 mmol) is added and the suspension is allowed to stir at RT for 30 min. To the solution is added iPr2NEt (1.57 mL, 9.02 mmol) and the mixture is allowed to stir at RT for 18 h. NaBH4 is added (0.164 g, 4.33 mmol) then the mixture is quenched with MeOH (1 mL), extracted with EtOAc (2×30 mL), washed with 1N HCl (4×50 mL), saturated NaHCO3 (2×50 mL) and brine (2×50 mL). The organic layer is dried over Na2SO4 and concentrated. The residue is purified by column chromatography, eluting with a gradient of 20-50% EtOAc/hexane as eluent to afford the title compound.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[O:6][C@H:7]([CH3:13])[C:8]([O:10]CC)=[O:9].Cl>O.CCO>[Cl:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[O:6][C@H:7]([CH3:13])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)[C@@H](C)Oc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of KOH (2.48 g, 44.2 mmol, 15 eq) in H2O (12 mL) was added ethyl (R)-2-(2,4-dichlorophenoxy)propionate (compound 9a; 0.80 g, 3.05 mmol) in EtOH (12 mL) at room temperature. The solution was stirred for 4 hours, and then acidified with concentrated aqueous HCl (pH 3). The resulting solid was filtered, rinsed with water, and dried to yield a white powder which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:26])=[CH:14][C:15]([F:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:17]=1)[N:5]=2.[C:27](Cl)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:27]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:26])=[CH:14][C:15]([F:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH:17]=1)[N:5]=2)(=[O:29])[CH3:28]
Reactant: Nc1nc2ccc(Oc3cc(NC(=O)C(F)(F)F)c(F)cc3Cl)nc2s1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)C(F)(F)F)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-2,2,2-trifluoroacetamide (2.03 g, 5 mmol) and N,N-dimethylpyridine-4-amine (0.61 g, 5 mmol) in pyridine (10 mL) was added dropwise acetyl chloride (0.78 g, 10 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), washed with water (50 mL×2), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether, collected by filtration, and dried under reduced pressure to give the title compound (2.16 g, 96%) as white powder crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:32])([F:31])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH:25]=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3.[BH4-].[Na+].CO>ClCCl>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:32])([F:31])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH2:25][OH:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nn(-c2ncccc2CO)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehyde (12.50 g, 26.10 mmol) in dichloromethane (125 mL) at 0° C. is added sodium borohydride (0.395 g, 10.44 mmol) and methanol (37.50 mL). The ice bath is removed and the reaction is stirred at room temperature for 30 min. Water (50 mL) is added and the mixture is concentrated to half volume resulting in a white sticky solid precipitate. Dichloromethane (100 mL) is added and the biphasic mixture is separated. The organic layer is washed with water (50 mL), dried over sodium sulfate and concentrated to half volume (around 100 mL). Methyl tert-butyl ether (100 mL) is added and the solution is concentrated to provide a precipitate. The solid is filtered and dried under vacuum to give 12 g of [2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol. MS (m/z): 481 (M+1).
Reaction SMILES: B(O)(O)O.[CH2:5]([OH:19])[C@@H:6]([OH:18])[C@@H:7]([OH:17])[C@H:8]([OH:16])[C@@H:9]([OH:15])[C@@H:10]([OH:14])[C:11]([O-:13])=[O:12].[Na+]>O>[CH2:5]([OH:19])[C@@H:6]([OH:18])[C@@H:7]([OH:17])[C@H:8]([OH:16])[C@@H:9]([OH:15])[C@@H:10]([OH:14])[C:11]([OH:13])=[O:12]
Reactant: O=C([O-])[C@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OB(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C

Procedure:
The diboron ester of glucoheptonic acid was prepared as follows: Approximately 124 grams (2 mols) of boric acid and 248 grams (1 mol) of sodium glucoheptonate were charged to an esterification vessel containing about 600 milliliters of water as a solvent. With stirring, the temperature was maintained at about 25° C. for approximately 30 minutes. The mixture was thereafter diluted to a final volume of one liter with additional water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1B(O)O.[F-].[Cs+].Br[C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:18][C:17]=1[O:29][CH2:30][CH2:31][CH2:32][CH3:33]>[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.COCCOC>[CH2:30]([O:29][C:17]1[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH:27]=[CH:28][C:16]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)c1ccc(Br)c(OCCCC)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCCCOC(=O)c1ccc(-c2cc(OC)ccc2F)c(OCCCC)c1
Temperature: 90 °C
Yield: 67.6 %

Procedure:
To a 2 dram vial charged with 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (2.323 g, 13.67 mmol), tetrakis(triphenylphosphine) palladium(0) (0.7897 g, 0.6834 mmol), cesium fluoride (0.8409 mL, 22.78 mmol), and 5.1 (1.50 g, 4.556 mmol), was added DME (20 mL), and the mixture was then heated at 90° C. overnight. The reaction was allowed to cool and then filtered and concentrated. The crude product was purified by combiflash (0 to 10% EtOAc/hexanes) yielding 5.2 (1.1530 g, 67.58% yield).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH3:30]>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][CH3:30])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: CCC(=N)NO
Product: CCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-propionamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.56 min; Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH3:26])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:8][CH:7]([CH3:24])[C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH3:26])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:8][CH:7]([CH3:24])[C:6]1=[S:29]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C(C)N1C(=O)C(C)N=C(c2ccccc2F)c2cc(Br)ccc21
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)N1C(=S)C(C)N=C(c2ccccc2F)c2cc(Br)ccc21

Procedure:
A mixture of 0.01 mole of 7-bromo-3,α-dimethyl-5-(o-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-bromo-3,α-dimethyl-5-(o-fluorophenyl)-2,3-dihydro-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)([N:15]1C=CN=C1)=O.[NH4+].[OH-]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:15])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cc2ccccc2[nH]1
Reaction time: 1 h

Procedure:
Add to a solution of indole-2-carboxylic acid 3 (31.0 mmol) and anhydrous THF (50 ml), carbonyldiimidazole (1.10 equiv., 5.5 g, 34.0 mmol). Stir for 1 h and add conc. NH4OH (50 mL) in one portion to the thick suspension. Stir at rt and after 16 h collect the solid by filtration, wash with H2O and dry in vacuuo at 40° C. to afford the indole-2-carboxamide 4 (R2═R3═H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([CH3:16])=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1.[BH4-].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.[OH-].[Na+]>O1CCCC1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:16])[N:13]([S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=4)(=[O:41])=[O:40])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1nc2cc(Cl)ccc2c2ccccc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)N2c3cc(Cl)ccc3-c3ccccc3C2C)c1
Temperature: 25 °C

Procedure:
A stirred solution of 3-chloro-6-methylphenanthridine (0.40 g, 1.76 mmol) in tetrahydrofuran (7 mL) was treated with freshly crushed sodium borohydride (0.33 g, 8.8 mmol). Trifluoroacetic acid (0.54 mL, 7.0 mmol) was added dropwise at a rate to keep the exothermic reaction and gas evolution under control. After the addition was complete the heterogeneous reaction mixture was stirred until the temperature returned to 23° C. The mixture was then heated at reflux for 14 hours. The reaction was cooled to room temperature and neutralized with a saturated, aqueous sodium bicarbonate solution (150 mL). The mixture was filtered through a plug of glass wool into a separatory funnel and extracted with diethyl ether (4×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a light brown paste. The crude 3-chloro-6-methyl-5,6-dihydrophenanthridine was dissolved in pyridine (12 mL), treated with 3-methoxybenzenesulfonyl chloride (0.55 g, 2.64 mmol) and 4-(dimethylamino)pyridine (0.01 g, 0.08 mmol), and stirred at 80° C. for 14 hours. The reaction mixture cooled to room temperature, treated with a 0.1 N aqueous sodium hydroxide solution (100 mL, 10 mmol), and extracted with dichloromethane (6×50 mL). The combined organic phase was washed with a 2 N hydrochloric acid solution (2×40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a brown solid. The brown solid was purified by flash column chromatography, eluting with a mixture of ethyl acetate:hexane (1:4), followed by crystallization from ethyl acetate-hexane, to afford the title compound as a homogeneous, white, crystalline solid (0.38 g, 54%), m.p. 117-118° C.;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[C:13](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O.CCCCCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
Under a nitrogen atmosphere, to a solution of 1H-indole-6-carboxylic acid (121 g, 752 mmol) in N,N-dimethylformamide (360 ml) was added potassium carbonate (124 g, 900 mmol), and the mixture was stirred at room temperature for 1 hr. Then, iodomethane (56 ml, 900 mmol) was added dropwise at room temperature over 15 min, and the mixture was stirred for 2 hr. Then, to the reaction solution were added water (1.2 L) and hexane (100 ml), and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, washed successively with water and hexane, and dried under reduced pressure to give the title compound (115 g, yield 87%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][CH2:10][C:11]1[NH:12][C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]([C:16]([OH:19])([CH3:18])[CH3:17])[N:15]=1)[CH3:8].[C:25]([N:44]1[C:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:55]2[CH:62]=[CH:61][C:58]([CH2:59]Br)=[CH:57][CH:56]=2)=[N:47][N:46]=[N:45]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C)C(=O)C.O>[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:59][C:58]2[CH:57]=[CH:56][C:55]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[C:48]3[N:44]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:45]=[N:46][N:47]=3)=[CH:62][CH:61]=2)[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]([C:16]([OH:19])([CH3:17])[CH3:18])[N:15]=1)[CH3:8]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
217 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 450 mg of ethyl 2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [prepared as described in Preparation 44(iii)] in 5 ml of N,N-dimethylacetamide, and the mixture was stirred for 30 minutes. At the end of this time, a solution of 1.47 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 10 ml of N,N-dimethylacetamide was added dropwise to the mixture. The mixture was stirred at room temperature for 2 hours, after which it was mixed with ethyl acetate and water and shaken. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.2 g of the title compound as an amorphous powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[CH:15][C:14]([CH:17](O)[CH2:18][CH2:19][CH3:20])=[C:13]([O:22][CH2:23][CH3:24])[CH:12]=1)[CH3:2].O=S(Cl)[Cl:27]>C(Cl)Cl>[Cl:27][CH:17]([C:14]1[C:13]([O:22][CH2:23][CH3:24])=[CH:12][C:11]([C:4]2[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:9][CH3:10])=[N:16][CH:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=S(Cl)Cl
Reactant: CCCC(O)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Solvent: ClCCl
Product: CCCC(Cl)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butan-1-ol (29 mg), and SOCl2 (0.2 mL) in CH2Cl2 (1 mL) is stirred at room temperature for one hour. The volatile materials are removed in vacuo to give 5-(1-chloro-butyl)-2-(2,6-diethyl-phenyl)-4-ethoxy-pyridine.
Reaction SMILES: [CH:1]1([N:4]([CH2:28][C:29]2[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:32]=[C:31]([O:40][CH2:41][CH2:42][O:43][CH:44]3[CH2:46][CH2:45]3)[CH:30]=2)[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[CH:1]1([N:4]([CH2:28][C:29]2[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:32]=[C:31]([O:40][CH2:41][CH2:42][O:43][CH:44]3[CH2:45][CH2:46]3)[CH:30]=2)[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(CN(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2c2ccn(C)c(=O)c2)C2CC2)cc(OCCOC2CC2)c1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)[C@@H]2CNCC[C@H]2c2ccn(C)c(=O)c2)C2CC2)cc(OCCOC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a CH2Cl2 solution (0.1 M) of trans-tert-butyl 3-({cyclopropyl[3-[2-(cyclopropyloxy)ethoxy]-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridinyl)-1-piperidinecarboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 4 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 93:7 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound. MS (ESI+, M+H): 538.