Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29](O)=[O:30])[C:23]=2[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:34](CC)CC)C.[Cl-].[NH4+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29]([NH2:34])=[O:30])[C:23]=2[CH:22]=[N:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 77.3 %

Procedure:
A suspension of 1-tritylpyrazolo[5,4-b]pyridine-4-carboxylic acid (3.996 g, 9.856 mmol) in DMF (70.01 mL) was treated sequentially with triethylamine (2.194 g, 3.022 mL, 21.68 mmol), ammonium chloride (2.636 g, 1.723 mL, 49.28 mmol) and TBTU (4.746 g, 14.78 mmol) at RT under nitrogen. The reaction was allowed to stir for 4 hours and then treated with DCM and saturated aqueous NH4Cl. The aqueous was extracted twice with DCM and the organic layer washed with aqueous NH4Cl, followed by 0.5M NaOH, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (70:9:1 DCM/MeOH/NH4OH) to give the product as white solid (3.08 g, 77% Yield). 1H NMR (DMSO, 400 MHz) δ 7.18-7.29 (15H, m), 7.44 (1H, m), 7.83 (1H, br s), 8.27 (1H, br s), 8.37 (1H, m), 8.46 (1H, m); MS (ES+) 405.12
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[OH-].[Na+].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>O.C(OCC)C>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:17]=[CH:18][C:7]([N:2]3[CH:6]=[CH:5][N:4]=[CH:3]3)=[CH:8][CH:9]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(NCCCCOc1ccc(-n2ccnc2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.8 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butylamine hydrochloride (Example 2) in 50 ml of water is treated successively with 4 ml of 10N NaOH and 2.0 g of 4-chlorobenzoyl chloride in 100 ml of diethyl ether. Stirring at room temperature for 3 hours gives a precipitate which is collected, washed with diethylether and water, and air dried. Recrystallization from 33% aqueous ethanol gives the desired product, m.p. 138°-139° C.; yield, 1.3 g.
Reaction SMILES: [C:1]([OH:16])(=[O:15])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH3:17][CH2:18][C@H:19]1[O:34][C:32](=[O:33])[C@H:31]([CH3:35])[C@@H:30]([O:36][C@@H:37]2[O:42][C@@H:41]([CH3:43])[C@H:40]([OH:44])[C@@:39]([O:46][CH3:47])([CH3:45])[CH2:38]2)[C@H:29]([CH3:48])[C@@H:28]([O:49][C@@H:50]2[O:55][C@H:54]([CH3:56])[CH2:53][C@H:52]([N:57]([CH3:59])[CH3:58])[C@H:51]2[OH:60])[C@@:27]([OH:62])([CH3:61])[CH2:26][C@@H:25]([CH3:63])[C:23](=[O:24])[C@H:22]([CH3:64])[C@@H:21]([OH:65])[C@@:20]1([OH:67])[CH3:66].O>O.C(O)C>[CH3:17][CH2:18][C@H:19]1[O:34][C:32](=[O:33])[C@H:31]([CH3:35])[C@@H:30]([O:36][C@@H:37]2[O:42][C@@H:41]([CH3:43])[C@H:40]([OH:44])[C@@:39]([O:46][CH3:47])([CH3:45])[CH2:38]2)[C@H:29]([CH3:48])[C@@H:28]([O:49][C@@H:50]2[O:55][C@H:54]([CH3:56])[CH2:53][C@H:52]([N:57]([CH3:58])[CH3:59])[C@H:51]2[OH:60])[C@@:27]([OH:62])([CH3:61])[CH2:26][C@@H:25]([CH3:63])[C:23](=[O:24])[C@H:22]([CH3:64])[C@@H:21]([OH:65])[C@@:20]1([OH:67])[CH3:66].[C:1]([O-:16])(=[O:15])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13]
Reactant: O=C(O)/C=C/CCCCCCCCC(=O)O
Agent: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: O
Solvent: CCO
Product: O=C([O-])/C=C/CCCCCCCCC(=O)[O-]
Temperature: 4 °C
Reaction time: 3 h

Procedure:
2.28 g of trans-traumatic acid (10 mmol) are suspended in 100 ml of water/ethanol 2:1 mixture at 4° C. 14.7 g of erythromycin free base (20 mmol) are added and the resulting mixture is kept under stirring at 4° C. for 3 hours and then heated to 25° C. overnight. 200 ml water ape then added. The mixture is concentrated under vacuum to a volume of about 100 ml and cooled to 4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:25]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])[CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Yield: 80.5 %

Procedure:
from 5-chloro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4d, 25 mg, 0.1 mmol) and 4-fluorophenylsulfonyl chloride (29.1 mg, 0.15 mmol). The HCl salt ether (32.6 mg, 74%) was prepared from the crude product using 1M HCl in ether. m.p 256-7° C., HRMS-FAB+ for C20H18N2O2SClF.HCl, calculated MH+ (--HCl): 405.08398; found: 405.0797.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: Brc1ccc(N2CCCCC2)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(N5CCCCC5)cc4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-1-yl-phenyl)-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 1-(4-bromo-phenyl)-piperidine (110.0 mg, 0.4581 mmol) in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.039 g, 25%). MP=229-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm):
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:17]3[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=3)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O)(=O)/C=C\C(O)=O>CO>[C:2]1([CH:8]2[C:17]3[C:12](=[C:13]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(=O)NC1c2c(Cl)cccc2C(c2ccccc2)CN1C
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CO
Product: CC(=O)NC1c2c(cccc2N2CCOCC2)C(c2ccccc2)CN1C
Yield: 70 %

Procedure:
A mixture of 7 g (0.02 mole) of 4-phenyl-8-chloro-acetylamino-2-methyl-1,2,3,4-tetrahydro-isoquinoline-hydrochloride, 70 ml of ethanol and 20 ml (20.0 g, 0.23 mole) of morpholine is refluxed for 5 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved in a mixture of 200 ml of water and 200 ml of ether, 30 ml of a 30% aqueous sodium hydroxide solution is added, the layers are separated and the aqueous phase is extracted four times with 200 ml of ether each. The united ether solutions are dried over anhydrous sodium sulfate and evaporated. The oily residue (6.7 g) is dissolved in 100 ml of ethanol and a solution of 6.6 g (0.057 mole) of maleic acid and 30 ml of methanol is added. The precipitated product is filtered in the cold. The beige coloured dimaleate (10.7 g) is dissolved in 100 ml of water, the solution is made alkaline by adding 60 ml of a 35% aqueous sodium hydroxide solution and extracted once with 200 ml and four times with 100 ml of ether each. The ether phases are united, dried over anhydrous sodium sulfate, clarified with activated charcoal and dried. The ether is evaporated and the residue is crystallized from a mixture of ether and petrolether. Thus 5.1 g of (0.014 mole) of white crystalline 4-phenyl-2-methyl-8-morpholino-acetylamino-1,2,3,4-tetrahydro-isoquinoline are obtained. Mp.: 120° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[NH:11][N:10]=[N:9][N:8]=2)=[N:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:10]1[N:9]=[N:8][C:7]([C:5]2[S:6][C:2]([Br:1])=[N:3][N:4]=2)=[N:11]1)[CH3:24]
Reactant: Brc1nnc(-c2nnn[nH]2)s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nnc(-c2nnc(Br)s2)n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazole (1 g, 4.3 mmol) in DMF (20 mL) was added Cs2CO3 (2.1 g, 6.45 mmol) and ethyl bromoacetate (0.95 mL, 8.6 mmol). The resulting solution was stirred at 90° C. for 1 hour. The mixture was partitioned between EtOAc (100 mL) and water (200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. Chromatography over silica afforded the title compound as a white solid, contaminated with the 1-alkylated isomer ethyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazol-1-yl]acetate. 1HNMR (CDCl3, 300 MHz): δ 5.70 (s, 2H), 4.26 (q, J=7 Hz, 2H), 1.28 (t, J=7 Hz, 3H).
Reaction SMILES: [CH:1]1([N:4]([C@@H:18]2[C@H:25]3[C@H:21]([CH2:22][NH:23][CH2:24]3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=O)=[CH:29][CH:28]=1.C(O)(=O)C.C([BH3-])#N>ClCCl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33]([C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:23]2[CH2:24][C@H:25]3[C@@H:18]([N:4]([CH:1]4[CH2:2][CH2:3]4)[S:5]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=4)(=[O:6])=[O:7])[CH2:19][CH2:20][C@H:21]3[CH2:22]2)=[CH:31][CH:32]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)[C@H]1CC[C@H]2CNC[C@H]21
Reactant: O=CCCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)[C@H]1CC[C@H]2CN(CCCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-Cyclopropyl-N-[(3aS*,4S*,6aR*)-octahydrocyclopenta[c]pyrrol-4-yl]-3-(trifluoromethyl)benzenesulfonamide from Example 201 (140 mg, 0.374 mmol) and 6,6-bis(4-fluorophenyl)hexanal (108 mg, 0.374 mmol) were combined in dichloromethane (2 mL) and then acetic acid (1 mL) was added. The reaction was stirred at room temperature for 20 minutes, then PS-cyanoborohydride (306 mg, 0.748 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the resin washed with dichloromethane. The solvent was removed in vacuo and the crude material purified using a silica gel cartridge (Analogix®, Burlington, Wis., RS-12) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.50 (s, 1H), 8.36 (d, J=7.9, 1H), 7.95 (d, J=7.9, 1H), 7.76 (dd, J=6.4, 14.2, 1H), 7.33 (dd, J=5.6, 8.3, 4H), 7.18-7.11 (m, 4H), 3.96 (dd, J=8.0, 16.3, 2H), 3.18-3.10 (m, 1H), 2.82 (dd, J=3.5, 9.5, 1H), 2.50-2.44 (m, 2H), 2.39 (t, J=8.0, 1H), 2.31-2.21 (m, 4H), 2.03 (dd, J=7.8, 15.3, 2H), 1.91 (dt, J=3.5, 10.4, 1H), 1.59 (dt, J=5.6, 11.5, 1H), 1.51 (dd, J=10.6, 16.2, 1H), 1.46-1.33 (m, 6H), 1.28 (dd, J=7.4, 15.1, 2H), 1.08 (td, J=5.0, 10.5, 1H), 0.84 (dt, J=6.9, 12.6, 1H), 0.75-0.66 (m, 1H); MS (ESI+) m/z 647 (M+H)+.
Reaction SMILES: O.[NH2:2][CH2:3][CH:4]1[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=32)[C:7](=[O:17])[NH:6][CH2:5]1.[CH3:18][C:19]([CH3:21])=O>O1CCCC1>[CH:19]([NH:2][CH2:3][CH:4]1[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=32)[C:7](=[O:17])[NH:6][CH2:5]1)([CH3:21])[CH3:18]
Reactant: NCC1CNC(=O)c2cccc3[nH]cc1c23
Reactant: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NCC1CNC(=O)c2cccc3[nH]cc1c23
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
0.82 g of borane-dimethylamine complex was added to a stirred solution of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole hydrate (see Example 1C for preparation) in 80 ml of tetrahydrofuran. The solution was heated under reflux for 1 hour and subsequently, at a temperature of 45° C., 10 ml of acetone were added dropwise. The reaction mixture was stirred at a temperature of 60° C. for 2.5 hours. To work up the reaction mixture it was subsequently evaporated to dryness, and the residue was dissolved in a mixture of water and dichloromethane. The dichloromethane phase was separated, and the aqueous phase was extracted three more times with 50 ml portions of a 9:1 dichloromethane/methanol mixture. The organic phases were combined and evaporated to dryness. The crude product which remained as residue was purified by chromatography under slightly elevated pressure (=flash chromatography) on silica gel using methanol/ethyl acetate 4:1 as eluent. The title compound was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].I[CH:33](C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH:28]([CH3:33])[CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CC(C)I
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting 2-iodopropane (20 equivalents iodide and sodium hydride with portion-wise addition) provided the title compound as a light yellow syrup. IR (liq.) 2971, 2935, 1564, 1552, 1497, 1471, 1392, 1379, 1368, 1206, 1177, 1140, 1123, 1101, 1061 cm−1; OAMS supporting ions at: ESI+ 470.2; MS (EI) m/z 469 (M+); HRMS (FAB) calcd for C26H29CL2N3O+H1 470.1766, found 470.1773. [α]25D=−93 (c 0.33, methylene chloride); Anal. Calcd for C26H29Cl2N3O: C, 66.38; H, 6.21; N, 8.93. Found: C, 66.53; H, 6.19; N, 8.89.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:22])[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])=[N:8][CH:7]=1)=[O:5].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH:4]([OH:5])[C:6]1[S:10][C:9]([NH:11][C:12](=[O:22])[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])=[N:8][CH:7]=1
Reactant: CCC(C(=O)Nc1ncc(C(=O)c2ccccc2Cl)s1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(C(=O)Nc1ncc(C(O)c2ccccc2Cl)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
N-[5-(2-Chloro-benzoyl)-thiazol-2-yl]-2-phenyl-butyramide (102 mg, 0.265 mmol) was suspended in 1 mL of anhydrous methanol. Sodium borohydride (30.3 mg, 0.801 mmol) was slowly added and the resulting pale yellow solution was allowed to stir for 1 hour at room temperature. After stirring for one hour a second aliquot of sodium borohydride (30.3 mg, 0.801 mmol) was added. The reaction mixture was allowed to stir for an additional hour and then the crude product was evaporated to dryness and then dissolved in a minimum of ethyl acetate. The organic layer was washed three times with an equal volume of 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was further purified by reverse-phase preparative liquid chromatography to yield the pure product (46 mg, 0.12 mmol, 45%) ESI-MS m/z calc. 386.1. found 387.3 (M+1)+ Retention time 3.83 minutes.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)(=[O:5])[CH3:4].Cl[CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24].O>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:11]([O:16][CH3:17])[CH:10]=1)(=[O:5])[CH3:4]
Reactant: COCCOCCl
Reactant: COc1cc(CCOC(C)=O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(CCOC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
0.9 g (23 mmol) of 60% sodium hydride is added in portions to a previously cooled solution of 4 g (19 mmol) of (4-hydroxy-3-methoxy-phenyl)-ethyl acetate in 20 ml of tetrahydrofuran and 20 ml of dimethylformamide. After stirring at room temperature for 45 minutes, 2.4 ml (21 mmol) of 1-chloromethoxy-2-methoxy-ethane is added dropwise. After stirring at room temperature for 1 hour, water and ethyl acetate are added. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. 5.5 g (97%) of [3-methoxy-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethyl acetate is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:4].[N+:18]([O-])([OH:20])=[O:19].C(OCC)(=O)C.CCCCCC>O>[CH3:17][CH:2]([CH3:1])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:18]([O-:20])=[O:19])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)C(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Ethyl 4-(2-methylpropionylamino)benzoate (Chemical Abstract 114(11) 101280u; Vagaonescu; Marisa, N-Acyl Derivatives of Anesthesin. Stud Univ. Banes-Bolyai Chem. 1989, 34, 12-14) was added slowly over a 50-min period to fuming nitric acid at 10° C. The reaction was stirred for 30 min at room temperature. Thin-layer chromatographic analysis (SiO2, 1:1 ethyl acetate:hexane) showed disappearance of the starting material along with the formation of a new higher-running spot (Rf =0.9). The reaction was poured into water and then extracted with ethyl acetate (3×500 mL). Next, the organic layer was washed with 1% sodium bicarbonate (500 mL) solution and then water (500 mL). The ethyl acetate layer was concentrated and the residue chromatographed (SiO2, 1:5 ethyl acetate:hexane). The fractions containing product were concentrated to give 17 g (49%) of ethyl 4-(2-methylpropionylamino)-3-nitrobenzoate as a yellow solid, mp 74°-76° C. An analytical sample was prepared by recrystallization from hexane. This material was collected by filtration and dried in vacuo at acetone reflux.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH2:8][C:9]3[C:14]([C:15]4([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].[C:35]([OH:47])(=[O:46])[CH2:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])([C:39]([OH:41])=[O:40])[OH:38]>CCOCC.O.N1C=CC=CC=1>[C:35]([OH:47])(=[O:46])[CH2:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])([C:39]([OH:41])=[O:40])[OH:38].[C:22]([O:1][C:2]1[C:7]2[CH2:8][C:9]3[C:14]([C:15]4([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCC2(CC1)c1ccccc1Cc1c(O)cccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1cccc2c1Cc1ccccc1C21CCN(C)CC1

Procedure:
4-Hydroxy-1'-methyl-9,10-dihydroanthracene-9-spiro-4'-piperidine (0.9 g.) is added to pyridine (7 ml.) and acetic anhydride (5 ml.) and the solution is warmed on the steam bath for 1 hour. It is then poured into water, basified with solid sodium carbonate, and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried (MgSO4), and evaporated to give an oil to which is added an excess of a saturated solution of citric acid in ether. The resulting solid is filtered off and recrystallised three times from methanol-ether to give 4-acetoxy-1'-methyl-9,10-dihydroanthracene-9-spiro-4'-piperidine citrate m.p. 156°-159°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][CH:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:48][N:47]=[N:46][N:41]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][C:29]([OH:32])([CH3:30])[CH3:31])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][CH:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 3′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.26 g), trimethylsilylazide (0.66 mL), dibutyltinoxide (0.060 g) and toluene (3 mL) was stirred at 100° C. for 20 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.9 mL) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and 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 a colorless amorphous solid (0.13 g, 46%).