Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:4][CH2:3]1.[CH:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+].O>C1COCC1>[CH:2]1([C:11]2([OH:21])[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH2:14][CH2:15][C:16]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]2=3)[CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: BrC1CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C2CC2)c2ccccc2CCc2ccccc21
Temperature: 60 °C
Yield: 52 %

Procedure:
In a three neck round bottom flask equipped with stirrer, (0.243 g, 0.009 mol) of magnesium turnings and 2.5 mL of dry THF was added. The reaction was stirred to allow the metal to dissolve. At this point the temperature was raised to 60° C. and cyclopropyl bromide (1.21 g, 0.010 mol) was added dropwise. The reaction mixture was allowed to reflux for 1.5 h at 70° C. and then lowered to 60° C. Then (1.04 g, 0.005 mol) of 10,11-dihydro-dibenzo[a,d]cyclohepten-5-one was added dropwise. Upon addition, the solution turned purple in color. The temperature was raised to 70° C. after addition was complete. The reaction refluxed for an additional 2 h and HPLC was used to monitor reaction progress. Ammonium chloride/H2O (7.5 mL) was added to quench the reaction and the flask placed in an ice bath. The resulting solution was filtered and the filtrate was transferred to a 250-mL separatory funnel charged with DCM (100 mL). Then finally NaCl/H2O solution (80 mL) was added. The organic phase was removed and dried over Na2SO4 for 2 h. The solvent was removed under reduced pressure and the product was dried under vacuum overnight. 1H NMR and LC/MS confirmed the product. (Yield ˜52%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:13](=[O:14])[C:12]2C(C(O)=O)=[C:16]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[S:17][C:11]=2[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:9]1=[O:36].CN(C)C=O>ClCCl>[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[C:1]([C:2]([Cl:4])=[O:3])=[C:16]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[S:17][C:11]=2[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:9]1=[O:36]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3cccc4ccccc34)sc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)Cl)c(Cc3cccc4ccccc34)sc21
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.092 ml) was added to a solution of 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid (Example 15a, 222 mg) and dimethylformamide (0.01 ml) in anhydrous dichloromethane (5 ml) at room temperature. After 2 hours, the solution was evaporated under reduced pressure to give 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carbonyl chloride as an oil. A solution of this oil (58 mg) in anhydrous dichloromethane (2 ml) was added to a stirred mixture of glycine methyl ester hydrochloride (29 mg) and triethylamine (0.037 ml) in anhydrous dichloromethane (1 ml) at room temperature. After 1 hour, ethyl acetate (25 ml) and 2M hydrochloric acid were added. The organic layer was washed with water then with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was dissolved in a mixture of tetrahydrofuran (4 ml), methanol (2 ml) and 1M sodium hydroxide solution (1 ml). After 2 hours, water (20 ml) was added and the solution was extracted with ether (20 ml). The aqueous layer was acidified with hydrochloric acid and then extracted with ethyl acetate (3×20 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallised from ethyl acetate:isohexane to give the title compound (42 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.C([Sn]([N:28]=[N+:29]=[N-:30])(CCCC)CCCC)CCC>>[NH:28]1[C:13]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:12]=[CH:11][CH:10]=2)=[N:14][N:30]=[N:29]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Product: Cc1ccc(-n2cccc2-c2nnn[nH]2)cc1

Procedure:
4-(2-(2H-2-trityltetrazol-5-yl)-1-pyrrolyl)-benzyl bromide is prepared as described in EP 0 480 204 A1 preparation 1 and 8, and as described in EXAMPLE 10. To this end 1-(4-methylphenyl)-2-cyanopyrrole is reacted with tributyltin azide to give 4-(2-(1H-tetrazol-5-yl)-1-pyrrolyl)-methylbenzene, which is protected by reaction with triphenylmethyl chloride. The benzylic methyl group of (2-(2H-2-trityltetrazol-5-yl)-1-pyrrolyl)-methylbenzene is then converted to the benzyl bromide with N-bromosuccinimide. An analog with a bromo substituent in the pyrrole ring is prepared from the same starting material 1-(4-methylphenyl)-2-cyanopyrrole by reaction with N-bromosuccinimide at room temperature to give 1-(4-methylphenyl)-4-bromo-2-cyanopyrrole. This is further reacted by analogy to the unsubstituted compound.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)(C)(C)C>CO.Cl>[CH3:6][NH:7][C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1
Reactant: CSc1ncc(N(C)C(=O)OC(C)(C)C)c(-c2ccccc2C)n1
Agent: Cl
Solvent: CO
Product: CNc1cnc(SC)nc1-c1ccccc1C
Yield: 93.9 %

Procedure:
A solution of 1.95 g (5.64 mmol) methyl-(2-methylsulfanyl-4-o-tolyl-pyrimidin-5-yl)-carbamic acid tert-butyl ester in 30 ml MeOH/HCl (2N) was stirred at 50° for 3 hr. After evaporation of the solvent, the residue was distributed between 40 ml 1N NaOH and 40 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 10:1) to give 1.30 g (94%) methyl-(2-methylsulfanyl-4-o-tolyl-pyrimidin-5-yl)-amine as a white solid, MS (EI): 245 (M+).
Reaction SMILES: [CH:1]12[CH2:29][CH:4]([CH:5]([CH2:7][NH:8][C:9]([C:11]3[C:12]([S:17][CH2:18][CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=4)=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:10])[CH2:6]1)[CH2:3][CH2:2]2.B(Br)(Br)Br>C(Cl)Cl>[CH:1]12[CH2:29][CH:4]([CH:5]([CH2:7][NH:8][C:9]([C:11]3[C:12]([S:17][CH2:18][CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=4)=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:10])[CH2:6]1)[CH2:3][CH2:2]2
Reactant: COc1ccc(CCCSc2ncccc2C(=O)NCC2CC3CCC2C3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCC1CC2CCC1C2)c1cccnc1SCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
A solution of 483 mg (1.18 mmol) of N-(5-bicyclo[2.2.1]heptanyl-methyl)-2-[3-(4-methoxyphenyl)-propylsulfanyl]-pyridine-3-carboxylic acid amide (exemplary compound 56) in DCM (50 ml) was cooled to −60° C.; 11.8 ml (11.8 mmol, 1M in DCM) of boron tribromide were added at that temperature and stirring was carried out for 90 min at −60° C. After warming to RT, the mixture was quenched with a 1M aq. NaHCO3 sol. and the phases were separated. The aqueous phase was extracted with EA and the organic phases were combined, washed with water, dried over MgSO4, filtered and concentrated in vacuo. Crystallization (hexane/EA 2:1) of the residue yielded 393 mg (0.99 mmol, 84%) of N-(5-bicyclo[2.2.1]heptanyl-methyl)-2-[3-(4-hydroxy-phenyl)-propylsulfanyl]-pyridine-3-carboxylic acid amide. MS: m/z 397.2 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1O.[N+:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[C-:13]>>[CH:13]1[N:1]2[C:10]3[C:5]([N:4]=[CH:3][C:2]2=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Oc1cnc2ccccc2n1
Product: CCOC(=O)c1ncn2c1cnc1ccccc12

Procedure:
M.p. 195°-196° C., from 2-quinoxalinol and ethyl isocyanoacetate. (Compound 2)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.[CH3:11][NH:12][CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Br:10][C:6]1[CH:5]=[C:4]([CH:2]([CH3:1])[N:12]([CH3:13])[CH3:11])[CH:9]=[CH:8][CH:7]=1
Reactant: CNC
Reactant: CC(=O)c1cccc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(c1cccc(Br)c1)N(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
60 g (0.30 mols) of 3-bromoacetophenone are dissolved in 800 ml of ethanol and mixed with 250 ml of dimethylamine. The pH of the solution is adjusted to 6.5 with acetic acid. The reaction mixture is then cooled to 0° and mixed with 19 g of sodium cyanoborohydride. After stirring for 2 days at room temperature, the reaction mixture is concentrated. The residue is mixed with 800 ml of water and acidified. The solution is then extracted twice with 400 ml of ether, the aqueous phase is rendered basic and extraction follows 3× with 400 ml of ether. The combined organic extracts are dried and concentrated. After distillation of the residue, the 3-bromo-N,N,α-trimethylbenzenemethanamine is obtained; b.p.: 98°-100°/10 mmHg.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3][CH:2]=1.[NH2:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=1.[BH4-].[Na+].C(O)(=O)C>C1(C)C=CC=CC=1.CO.O>[N:1]1[CH:6]=[C:5]([CH2:7][NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=Cc1cncnc1
Reactant: Cc1cccnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccnc1NCc1cncnc1
Temperature: 80 °C
Yield: 96.1 %

Procedure:
To a solution of 5-pyrimidinecarboxaldehyde (5.0 g, 46 mmol) in toluene (100 mL) was added 2-amino-3-picoline (5.0 g, 46 mmol). The reaction mixture was heated to 80° C. on a rotary evaporator while under reduced pressure. After 10 min an additional 200 mL of toluene was added. Continued heating under reduced pressure resulted in a white solid which was dissolved in methanol (200 mL). This solution was stirred vigorously under a nitrogen atmosphere, and granular sodium borohydride (10.0 g, 265 mmol) was added portionwise, resulting in vigorous bubbling. The reaction was allowed to stir for 1 h at room temperature after completion of the sodium borohydride addition. Acetic acid (1 mL) was then added, and the reaction mixture was stirred for 5 min, followed by the addition of water (100 mL). The volatiles were removed under reduced pressure, and the aqueous suspension was extracted with dichloromethane (2×100 mL). The organic layers were combined and dried over MgSO4, filtered, and the solvent was removed under reduced pressure to yield an off-white solid. The crude solid was adsorbed onto Celite® and purified by column chromatography (gradient of 100% hexanes to 100% ethyl acetate over 30 minutes) to yield 8.848 g of a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(N)C1=O
Product: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
Following the same procedure described in Example 42(h), 0.4 g of t-butyl α-[6-amino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 49(g)] was N-alkylated using 0.80 g of benzyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography eluted with a 1:40 by volume mixture of ethyl acetate and methylene chloride to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[N:3]=1.[NH2:21][C:22]1[CH:26]=[C:25]([C:27]#[N:28])[NH:24][N:23]=1.CO>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:26]=[C:25]([C:27]#[N:28])[NH:24][N:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: N#Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccccc2n1
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
A mixture of (4-chloroquinazoline-2-yl)(4-fluorophenyl)methanone from Example 3 (580 mg, 2.02 mmol), and 3-amino-1H-pyrazole-5-carbonitrile (218 mg, 2.02 mmol) in DMF (5 mL) was stirred at rt overnight. MeOH (10 mL) was then added to this mixture, and the precipitate was filtered washed with MeOH, and dried to afford 3-(2-(4-fluorobenzoyl)quinazolin-4-ylamino)-1H-pyrazole-5-carbonitrile (170 mg, 23.4%) 1H NMR (300 MHz, DMSO-d6) δ 6.89 (s, 1H), 7.40 (d, 2H), 7.83 (s, 1H), 7.98 (m, 2H), 8.11 (m, 2H), 8.56 (s, 1H), 11.18 (s, 1H), 13.84 (s, 1H); LC-MS (ESI) m/z 359 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17](O)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH:31]1[CH2:36][CH2:35][CH:34]([C@:37]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)([OH:39])[CH3:38])[CH2:33][CH2:32]1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([N:31]4[CH2:36][CH2:35][CH:34]([C@:37]([C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)([OH:39])[CH3:38])[CH2:33][CH2:32]4)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: C[C@](O)(c1cccnc1)C1CCNCC1
Reactant: O=C(O)[C@@]12C[C@@H](c3ccccc31)c1ccc(Cl)cc12
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@](O)(c1cccnc1)C1CCN(C(=O)C23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (9S,10S)-2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid, prepared as in Example 11 (1.25 g, 4.61 mmol) in dichloromethane (20 mL) was treated with oxalyl chloride (731 mg, 5.76 mmol) and N,N-dimethylformamide (10 mg, 0.14 mmol). The resulting solution was warmed to reflux temperature for 2 h, then was cooled to room temperature and the excess reagent was evaporated in vacuo. The residue was dissolved in tetrahydrofuran (10 mL) and added dropwise to a solution of (R*)-1-(4-piperidyl)-1-(3-pyridyl)ethanol (950 mg, 4.61 mmol) and triethylamine (582 mg, 5.76 mmol) in tetrahydrofuran (15 mL) and dichloromethane (25 mL). The resulting mixture was stirred for 3 h at room temperature, then was poured into 1N aqueous sodium hydroxide (25 mL) and extracted with chloroform (3×100 mL) The organic extracts were washed sequentially with 1N aqueous sodium hydroxide (50 mL) and brine (50 mL), combined, dried over sodium sulfate, filtered and evaporated to leave a dark tan foam. Purification by flash chromatography (eluant: 1:1 hexane/acetone) afforded the title amide as an off white foam (2.00 g, 4.36 mmol, 95%). CIMS: m/z 461 ((M+H)+, 37Cl, 33%), 460 ((M+H+1)+, 35Cl, 28), 459 ((M+M)+, 35Cl, 100).
Reaction SMILES: [N:1]1([C:7](OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:29]=C(Cl)[N:27]=[CH:26][N:25]=1>ClCCl>[Cl:23][C:24]1[CH:29]=[C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)[N:27]=[CH:26][N:25]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCNCC2)ncn1
Temperature: 25 °C
Yield: 98 %

Procedure:
13.3 g tert-butyl 1-piperazinecarboxylate and 11.2 mL DIPEA were added to 10 g 4, 6 dichloro pyrimidine in 1000 mL dichlormethane was stirred over the weekend at RT. The solvent was removed. The residue was dissolved in 200 mL dichlormethane and 200 mL trifluoro acetic acid was added. The reaction was stirred at RT. The solvent was removed. The residue was dissolved in methanol and passed through HCO3 containing resin. The solvent was removed and the residue was purified by chromatographie on silica (dcyclohexane: ethylacetate 0-40%) to yield 13.07 g of the desired product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([CH3:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C>Cl>[CH3:15][N:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH2:5][CH2:6]2)[CH3:14]
Reactant: CC(=O)N1CCc2cc(N(C)C)ccc21
Agent: Cl
Product: CN(C)c1ccc2c(c1)CCN2
Yield: 60.8 %

Procedure:
1-Acetyl-5-(N,N-dimethylamino)indoline (D12) (0.6 g, 2.94 mmol) in conc. HCl (0.6 ml) was heated over a steam bath for 45 min. The mixture was partitioned between sat aq. K2CO3 (50 ml) and CHCl3 (50 ml) the organic solution dried (Na2SO4), evaporated to dryness under reduced pressure and purified by column chromatography (SiO2, EtOAc/MeOH 5-10%) to afford the title compound (290 mg, 61%) which was used directly in Example 4.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][N:30]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:19][C:20]5([CH2:21][CH2:22][N:23]([C:29]6[N:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][N:30]=6)[CH2:24][CH2:25]5)[CH2:26]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: CCCc1cnc(Cl)nc1
Product: CCCc1cnc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)nc1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-chloro-5-n-propyl-pyrimidine following a procedure analogous to that described for Example 15. LC (method 3): tR=0.88 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH2:1])=[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]([CH3:19])=[N:5]2)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3C(C)=O)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate (Example 92b) and acetic anhydride as brown solid (28%). MS 372 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[N:23](COCC[Si](C)(C)C)[N:22]=1>O1CCCC1.C(#N)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:12][N:11]=[N:10][N:9]=4)=[CH:4][CH:3]=3)[CH:28]=2)[NH:23][N:22]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Brc1ccc(-c2nnn[nH]2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(-c4nnn[nH]4)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.1 %

Procedure:
In a microwave vial 5-(4-bromo-phenyl)-1H-tetrazole (89.2 mg, 0.4 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.40 mmol) in tetrahydrofuran/acetonitrile/1 N aqueous sodium bicarbonate (4 ml) was degassed with nitrogen and 1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (32.4 mg, 0.04 mmol) was added and the vial sealed. This reaction mixture was irradiated to 150° C. for 30 minutes in a microwave reactor. The mixture was extracted with ethyl acetate (3×) and the combined organic layers were dried over magnesium sulfate and filtered through a silica gel plug MS: m/z 500.6 (M+H+). To this crude was added trifluoroacetic acid (1 ml) and the reaction mixture stirred for 16 hours at ambient temperature. The solvent was removed under reduced pressure and the resulting solid was purified by preparative mass-triggered reverse-phase HPLC to yield 3-(2-methoxy-phenyl)-5-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrazolo[3,4-b]pyridine as a white solid (7.5 mg, 5%). 1H NMR (500 MHz, DMSO-d6) δ 3.87 (s, 3H); 6.56 (s, 3H); 7.11 (t, J=8 Hz 1H) 7.23 (d, J=8 Hz 1H); 7.48 (t, J=8 Hz, 1H); 7.66 (d, J=8 Hz 1H); 8.01 (t, J=9 Hz, 1H); 8.14 (d, J=9 Hz 1H); 8.44 (s, 1H); 8.94 (s, 1H); 13.84 (s, br, 1H); MS: m/z 369.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([OH:24])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.CC1(C)O[C@]2(OC[C@@H]3OC(C)(C)O[C@@H]3C2=O)CO1>CCOCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([OH:24])[C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(O)c1ccc(C(F)(F)F)cc1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Agent: CC1(C)O[C@H]2CO[C@@]3(COC(C)(C)O3)C(=O)[C@H]2O1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](C(=O)O)[C@H](O)c1ccc(C(F)(F)F)cc1
Yield: 34 %

Procedure:
To a solution of (R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propanoic acid (LXXVIII) (35 g, 100 mmol) in Et2O (600 mL) was added quinine (34 g, 100 mmol) in portions. The reaction was stirred at room temperature for 30 min at which time the white precipitate (L-enantiomer salt) was filtered and washed with Et2O. The solid was taken up in EtOAc/aqueous KHSO4. The organic layer was washed with aqueous KHSO4, brine and dried over MgSO4. The solvent was removed in vacuo to give optically pure (Marfey test) (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propanoic acid (LXXIX) (12 g, 34 mmol, 68% yield). 1H NMR (DMSO-d6) δ ppm 1.33 (s, 9H), 4.09 (brs, 1H), 5.13 (brs, 1H), 5.56 (brs, 1H), 7.47 (d, J=8 Hz, 2H), 7.56 (d, J=8 Hz, 2H); 19F NMR (DMSO-d6) δ ppm −60.15; ESIMS found for C15H18F3NO5 m/z 348 (M−H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:13]([O:15]C=O)C>C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]=[O:15]
Reactant: CCOC=O
Reactant: NCCCCCCCCCCN
Solvent: CCO
Product: NCCCCCCCCCCNC=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,10-diaminodecane (6.88 g, 40 mmol) were dissolved in 100 ml of ethanol and 3.22 ml of ethylformate was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours and evaporated to dryness. The residue was chromatographed on a silica gel column using 25% methanol/methylenechloride as the eluent to obtain 4 g of the title product.