Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][CH:25]1[CH2:30][NH:29][CH:28]([CH3:31])[CH2:27][NH:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:24][CH:25]1[CH2:30][NH:29][CH:28]([CH3:31])[CH2:27][N:26]1[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: CC1CNC(C)CN1
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC1CN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C(C)CN1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 2,5-dimethylpiperazine (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 15-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (41 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.57 Hz, 3H) 1.36 (d, J=6.82 Hz, 3H) 1.46 (s, 6H) 3.17 (d, J=5.81 Hz, 1H) 3.60 (dd, J=13.14, 5.31 Hz, 2H) 3.73 (br. s., 1H) 3.93 (dd, J=13.14, 2.78 Hz, 1H) 4.62 (d, J=4.55 Hz, 1H) 6.44 (d, J=2.27 Hz, 1H) 7.51 (s, 1H) 7.61 (d, J=8.59 Hz, 2H) 8.00 (d, J=8.34 Hz, 2H) 8.13 (d, J=2.27 Hz, 1H) 8.94 (br. s., 1H) 9.04 (br. s., 1H) 11.04 (s, 1H). ESI-MS: m/z 409.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([SH:21])[N:15]=1>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([S:21][C:16]3[N:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH3:13])[N:15]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(C)nc(S)n1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: Cc1cc(C)nc(Sc2ccnc3cc(Cl)ccc23)n1
Temperature: 80 °C

Procedure:
A mixture of 1.17 g of 4,7-dichloroquinoline, 1.0 g of 4,6-dimethyl-2-mercaptopyrimidine and 3 ml of N,N-dime thylimidazolidinone was heated at 80° C. for 1 hour. The reaction mixture was cooled and separated by column chromatography(n-hexane/ethyl acetate=1/1) to obtain 7-chloro-4-(4,6-dimethyl-2-pyrimidinylthio)-quinoline. Yield was 0.83 g. Melting point was 127.4°-129.5° C.
Reaction SMILES: Br[C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:8]1[CH:7]2[CH:2]1[C:3]([CH3:20])([CH3:19])[O:4][C:5]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:9][C:6]=12
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)[C@@H](O)[C@H](Br)C(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C1OC1C(C)(C)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.5 %

Procedure:
A mixture of trans-3-bromo-3,4-dihydro-4-hydroxy-N,N,2,2-tetramethyl-2H-1-benzopyran-6-sulfonamide (19.2 g), potassium carbonate (15 g) and dimethylformamide (153 ml) was stirred at room temperature for 24 hours and followed by at 35° C. for 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated to give 3,4-dihydro-3,4-epoxy-N,N,2,2-tetramethyl-2H-1-benzopyran-6-sulfonamide (4.7 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH:17]=[CH:18][N+:19]([O-])=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:17][CH2:18][NH2:19]
Reactant: O=[N+]([O-])C=Cc1c[nH]c2c(F)cccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCc1c[nH]c2c(F)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
Combine lithium aluminum hydride (12.8 g; 336.1 mmol) and 0° C. anhydrous tetrahydrofuran (160 mL). Cool resulting exotherm to 0° C. Add 7-fluoro-3-(2-nitrovinyl)-1H-indole (11.55 g, 56.0 mmol) in anhydrous THF (200 mL) dropwise. After 30 min, warm to ambient temperature. After 4 hours, cool to 0° C. and add saturated sodium sulfate solution (35 mL) dropwise. Filter the solids and wash with THF and ethyl acetate. Concentrate the filtrate and dissolve the residue in methylene chloride. Filter the precipitate to give 1.26 g of product as brown crystals. Concentrate the filtrate and chromatograph on silica gel eluting with 5%, 7%, 10% 2N ammonia in methanol/methylene chloride to give product: MS (m/e): 179 (M+1), 177 (M−1); Calculated for C10H11FN2: Calcd: C, 67.40; H, 6.22; N, 15.72. Found: C, 67.06; H, 6.11; N, 15.48.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]([OH:27])=O.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1)([O-:30])=[O:29]>C1COCC1.CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]([N:40]1[CH2:41][CH2:42][N:37]([C:34]2[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=2)[CH2:38][CH2:39]1)=[O:27]
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CC(=O)N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)c2c1
Reaction time: 1 h
Yield: 91 %

Procedure:
In a 100 ml flask, 1.62 g (10 mmoles) of 1.1′-carbonyl-diimidazole is added to a solution of 2.05 g (10 mmoles) of 5-methoxyindole-3-acetic acid in 10 ml of THF. After one hour of agitation at ambient temperature, a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMF is added dropwise. Agitation is continued for 15 hours. The reaction medium is then concentrated under vacuum and the evaporation residue is precipitated from 50 ml of an ethyl acetate/water mixture (1/1). After filtration, the solid is rinsed successively with 50 ml of water, 50 ml of ethyl acetate and 50 ml of dichloromethane. After drying under vacuum, a yellow powder is obtained with a yield of 91%. Melting point: 239-240° C.
Reaction SMILES: [C:1]([NH:8][CH:9]([CH:13]1[CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14]1)[CH:10]1[CH2:12][CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([NH:8][CH:9]([CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[CH:10]1[CH2:11][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(C1CC1)C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C1CC1)C1CCNC1
Reaction time: 42 h
Yield: 35.1 %

Procedure:
A sample (548 mg) of the compound from step 470d was dissolved in methanol, 140 mg of 10% Pd/C was added, and the mixture was hydrogenated at 4 atm H2 for 42 hours at room temperature. The solution was filtered, and the solvent was removed to give 140 mg of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:17]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31]CC3C=CC=CC=3)[CH:24]=2)[N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:17]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([OH:31])[CH:24]=2)[N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C(c2ccc(OC)c(OCc3ccccc3)c2)n2cncn2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(c2ccc(OC)c(O)c2)n2cncn2)cc1O

Procedure:
10% Pd/C (80 mg) was added to a solution of 1-[bis-(3-benzyloxy-4-methoxyphenyl)methyl]-1H-[1,2,4]triazole (1.65 g, 3.25 mmol) in THF/MeOH (1:1, 200 mL). The solution was stirred under an atmosphere of H2 (provided by addition from a balloon) overnight. The excess H2 was removed and the reaction mixture was filtered through Celite® washing with THF and MeOH, then the solvent was removed in vacuo. The crude product was purified using Flashmaster II (EtOAc/Hexane) to give the title compound STX1003 (0.86 g, 81%, mp 217.5-219° C.) as a white solid; δH (270 MHz, d6-DMSO) 9.08 (2H, s, 2×OH), 8.47 (1H, s, NCHN), 8.03 (1H, s NCHN), 6.88 (2H, d, J=8.4, ArH), 6.76 (1H, s, CH), 6.64 (2H, s, ArH), 6.57 (2H, d, J=8.4, ArH), 3.74 (6H, s, 2×CH3); δC (68 MHz, d6-DMSO) 151.8 (CH), 147.3 (2×C), 146.3 (2×C), 144.0 (CH), 130.1 (2×C), 118.8 (2×CH), 115.3 (2×CH), 111.9 (2×CH), 64.9 (CH), 55.6 (2×Ch3); LCMS (ES−) 326.2 ([M−H]−, 100%), 255.9 (70), 240.4 (60), 211.4 (70); HRMS (FAB+) Found 327.1226, C17H17N3O4 requires 327.1219; HPLC (CH3CN/H2O, 90:10) tR=1.57 min 99+%); Found: C, 62.10%, H, 5.26%; N, 12.80%, C17H17N3O4 requires: C, 62.38%; H, 5.23%; N, 12.84%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=2[O:9][CH:8]=1)(=O)=O.[C:20]([Si](C)(C)C)#[C:21][CH2:22][CH3:23]>>[C:20]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=2[O:9][CH:8]=1)#[C:21][CH2:22][CH3:23]
Reactant: COc1cccc2c(OS(=O)(=O)C(F)(F)F)coc12
Reactant: CCC#C[Si](C)(C)C
Product: CCC#Cc1coc2c(OC)cccc12

Procedure:
The title compound was prepared from 7-methoxybenzofuran-3-yl trifluoromethanesulfonate and Intermediate 39 following General Procedure B. 1H NMR (DMSO-d6, 400 MHz): δ 8.24 (s, 1H), 7.26 (t, 1H), 7.17 (d, 1H), 6.99 (d, 1H), 3.94 (s, 3H), 2.52-2.47 (m, 2H), 1.21 (t, 3H). LCMS: 201 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[CH:11]1[CH2:12][NH:8][CH2:9][CH:10]1[CH:21]([OH:23])[CH3:22]
Reactant: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(F)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1CNCC1c1ccc(F)cc1F
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a solution of 1-[(3SR,4RS)-1-benzyl-4-(2,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanone (IX-14) (1.87 g, 5.92mmol) in THF (30 mL) at 0° C. were added portion wise LiAlH4 (0.19 g, 5.21 mol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (SR)-1-[(3SR,4RS)-4-(2,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-14) 0.72 g (38%) as a white solid ES-MS m/e: 318.1 (M+H+) and (RS)-1-[(3SR,4RS)-4-(2,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (X-A-14) 0.374 g (19%) as a white solid ES-MS m/e: 318.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.[OH:25][CH2:26][C@@H:27]([NH:29][C:30]([NH2:32])=[NH:31])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:32]=[C:30]([NH:29][C@@H:27]([CH3:28])[CH2:26][OH:25])[N:31]=2)[CH2:3][CH2:2]1
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Reactant: C[C@@H](CO)NC(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](CO)Nc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one (9) (50 mg, 0.155 mmol) in DMF (541 μl), (S)-1-(1-hydroxypropan-2-yl)guanidine (147 mg, 0.773 mmol) and potassium carbonate (214 mg, 1.546 mmol) were added, and the reaction mixture was stirred at 90° C. for 3 hours. The crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (23.9 mg, 41%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][C:34]#[N:35])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:50]=[N+:51]=[N-:52])(C)C>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][C:34]5[NH:52][N:51]=[N:50][N:35]=5)[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: N#CCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(c1ccn2c1CSC2c1cccnc1)c1cn(Cc2nnn[nH]2)c2cc(-c3ccc(F)cc3)ccc12
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A mixture of 3(pyridin-3-yl)-7-[1-cyanomethyl-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (77 mg, 0.161 mmol), prepared as in Example 94, dibutyltin oxide (40 mg, 0.161 mmol), and trimethylsilylazide (47.3 μL, 0.322 mmol) in toluene (15 mL) was heated at reflux for three hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude product was azeotroped with CH2Cl2 and purified by flash chromatography on silica gel (9:1 CHCl3, methanol) to give 3-(Pyridin-3-yl)-7-[1-(1H-tetrazol-5-ylmethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (53 mg), m.p. 110°-118° C. 1H NMR (D3COD, 300 MHz) δ45 (d; 1H, J=15 Hz), 4.63 (dd, 1H, 15, 3 Hz), 5.75 (s, 2H), 6.57 (d, 1H, J=3 Hz), 6.67 (bs, 1H), 6.98 (d, 1H, J=3 Hz, 7.15 (t, 2H, J=9 Hz), 7.45-7.51 (m, 2H), 7.67-7.77 (m, 3H), 7.79 (s, 1H), 8.25 (s, 1H), 8.31 (d, 1H, 9 Hz), 8.55 (bs, 2H). MS (FAB) m/e 522 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:18]=1)=[C:10]([CH3:33])[CH:9]=2)=[O:5])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:32])[CH:18]=1)=[C:10]([CH3:33])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(C(=O)c4ccc(F)cc4)c3)c(C)cc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(C(O)c4ccc(F)cc4)c3)c(C)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of 5-[3-(4-Fluoro-benzoyl)-4-hydroxy-phenoxy]-4,6-dimethyl-1H-indole-2-carboxylic acid ethyl ester (20 mg, 0.045 mmol) in ethanol (1 mL) at room temperature was added sodium borohydride (3.4 mg, 0.089 mmol), and the resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with 1M HCl.(10 mL), diluted with ethyl acetate (10 mL). The ethyl acetate layer was separated, washed with 1M HCl (2 times 10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography (4% methanol in methylene chloride) to afford the title compound (17.5 mg) as a solid. 1H NMR (400 MHz, CDCl3) δ8.76 (s, 1H), 7.31-7.23 (m, 2H), 7.17 (s, 1H), 7.05 (s, 1H), 6.98 (t, 2H), 6.72 (d, 1H), 6.50 (dd, 1H), 6.36 (d, 1H), 5.84 (s, 1H), 4.40-4.34 (q, 2H), 2.25 (s, 3H), 2.14 (s, 3H), 1.38 (t, 3H). MS (APCI−) Calc:449.2, Found: 448.3 (M−1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[CH2:9][N:8](CC3C=CC(OC)=CC=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(O[K])(C)(C)C.C(OCC)(=O)C>CN1C(=O)CCC1>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[C:3]3[CH:10]([CH3:11])[CH2:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(CN2CC(C)c3c(Cl)ncnc32)cc1
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1CNc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 128 °C
Yield: 50 %

Procedure:
To a solution of 4-Chloro-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.55 g, 1.88 mmol) in NMP (20 mL) were added 1-Boc-piperazine (1.0 g, 5.40 mmol) and tBuOK (0.21 g, 1.88 mmol). The mixture was heated to 128° C. for 30 hours. After cooling, the mixture was diluted by ethyl acetate (500 mL) and washed with water (5×150 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 4-(5-Methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 36%). 1H NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.52 (dd, J=27.6 Hz, J=14.8 Hz, 2H), 3.79 (s, 3H), 3.58 (m, 12H), 3.34 (m 1H), 2.95 (m, 1H), 1.48 (s, 9H), 1.15 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H]+440.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[C:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[H][H]>CC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: OCC#CCc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CC(C)=O
Product: OC/C=C\Cc1ccc(Cl)cc1

Procedure:
Dissolve 10 g (0.055 mole) of 4-(4-chlorophenyl)but-2-yn-1-ol in 100 ml of acetone. Add 0.6 g of Lindlar's catalyst. Stir the mixture under 1 atmosphere of hydrogen at room temperature. Follow the progress of the reaction by NMR. At the completion of the reaction, filter to remove the catalyst and evaporate to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:2]3=[N:26]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCC2
Reactant: COc1ccc(NN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc3c4c([nH]cc-3c2=O)CCCC4)cc1

Procedure:
A mixture of 5.44 g of ethyl 4-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylate and 3.45 g of 4-methoxyphenylhydrazine is refluxed 18 hrs in 100 ml toluene. The resulting mixture is stirred with 50 ml 1N NaOH, the layers separated, and the aqueous phase extracted twice with ether. The aqueous layer is then neutralized with aqueous ammonium chloride and filtered. The product is washed with water, and dried to give 2-(4-methoxyphenyl)-2,3,6,7,8,9hexahydropyrazolo[4,3-c]quinolin-3(5H)-one p.p. 279°-282°.
Reaction SMILES: FC1C(F)=CC(C2C=CC(OCC3C=C4C(C=CN4CCC(O)=O)=CC=3)=CC=2)=C(OC)C=1.C([O:35][C:36](=[O:66])[CH2:37][CH2:38][N:39]1[C:47]2[C:42](=[C:43]([CH2:48][O:49][C:50]3[CH:55]=[CH:54][C:53]([C:56]4[CH:61]=[C:60]([F:62])[C:59]([F:63])=[CH:58][C:57]=4[O:64][CH3:65])=[CH:52][CH:51]=3)[CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40]1)C>>[F:63][C:59]1[C:60]([F:62])=[CH:61][C:56]([C:53]2[CH:54]=[CH:55][C:50]([O:49][CH2:48][C:43]3[CH:44]=[CH:45][CH:46]=[C:47]4[C:42]=3[CH:41]=[CH:40][N:39]4[CH2:38][CH2:37][C:36]([OH:66])=[O:35])=[CH:51][CH:52]=2)=[C:57]([O:64][CH3:65])[CH:58]=1
Reactant: CCOC(=O)CCn1ccc2c(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cccc21
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(CCC(=O)O)c3c2)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3CCC(=O)O)cc1

Procedure:
3-[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid was synthesized by a procedure similar to 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid from starting material 3-[4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester to yield the product as a white solid (23 mg, 82%). LC-MS (ES) calculated for C25H21F2NO4, 437.1; found m/z 438 [M+H]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[C:24]12([C:34]3[S:38][C:37]([NH2:39])=[N:36][N:35]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>>[C:24]12([C:34]3[S:38][C:37]([NH:39][C:1]([C:4]45[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]6[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]6[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]4)[CH2:8][CH2:9]5)=[O:3])=[N:36][N:35]=3)[CH2:25][CH:26]3[CH2:27][CH:28]([CH2:29][CH:30]([CH2:32]3)[CH2:31]1)[CH2:33]2
Reactant: Nc1nnc(C23CC4CC(CC(C4)C2)C3)s1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nnc(C45CC6CC(CC(C6)C4)C5)s3)(CC1)CC2
Yield: 67.8 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 5-adamantyl-2-amino-1,3,4-thiadiazole (80.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(5-adamantyl-1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2)oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (56.7 mg).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[Cl:13][C:14]1[S:38][C:17]2[NH:18][C:19]([C:21]([NH:23][CH:24]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:34][C:35]#[N:36])[C:25]3=[O:37])=[O:22])=[CH:20][C:16]=2[CH:15]=1>CN1CCCC1=O.CCOC(C)=O>[Cl:13][C:14]1[S:38][C:17]2[NH:18][C:19]([C:21]([NH:23][CH:24]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:34][C:35]4[NH:36][N:3]=[N:2][N:1]=4)[C:25]3=[O:37])=[O:22])=[CH:20][C:16]=2[CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2ccccc2N(Cc2nnn[nH]2)C1=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 150 °C
Yield: 73.7 %

Procedure:
Sodium azide (178 mg, 2.73 mmol) and triethylamine hydrochloride (356 mg, 2.59 mmol) were added to 2-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 27; 300 mg, 0.78 mmol) in 1-methyl-2-pyrrolidinone (7 mL) and then heated at 150° C. for 3 hours. On cooling the mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL). The aqueous layer was acidified with citric acid and extracted with MeOH:DCM (1:19) and the combined organics dried (MgSO4), filtered and evaporated. The residue was purified by applying the material to a 10 g Isolute NH2 column in MeOH:DCM (1:9) (10 mL) and eluting with MeOH:DCM (1:9) (6×10 mL). The column was eluted with MeOH: 2M HCl in Et2O:DCM (5:4:45) (6×10 mL) and the relevant fractions evaporated to afford the title product (246 mg, 74%) as pale pink powder.