Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16](=[O:34])[N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:19][CH2:18]3)[C:12](O)=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16]([N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:21][CH2:22]3)=[O:34])[C:12]([N:45]3[CH2:46][CH2:47][CH:42]([CH:39]4[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]4)[CH2:43][CH2:44]3)=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN1CCC(C2CCNCC2)CC1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCC2
Product: CN1CCC(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from and 2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-methyl-[4,4′]bipiperidinyl.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20](F)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=CC2C3N=C(C(N)=O)SC=3CCOC=2C=1.[CH3:44][N:45]1[CH2:50]CC(NN)[CH2:47][CH2:46]1>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]5[CH2:47][CH2:46][N:45]([CH3:50])[CH2:44][CH2:20]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CN1CCC(NN)CC1
Agent: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)CC1

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with (1-methyl-piperidin-4-yl)-hydrazine to give 8-Bromo-2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([O:37][CH3:38])[CH2:36][O:35][CH2:34]2)[CH:30]=[C:29]([F:39])[C:28]=1[C:40]1[N:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=1[F:49]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:46](=[O:47])[C:44]2[CH:43]=[CH:42][C:41]([F:49])=[C:40]([C:28]3[C:29]([F:39])=[CH:30][C:31]([C:33]4([O:37][CH3:38])[CH2:36][O:35][CH2:34]4)=[CH:32][C:27]=3[F:26])[N:45]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: COC1(c2cc(F)c(-c3nc(C(=O)O)ccc3F)c(F)c2)COC1
Product: COC1(c2cc(F)c(-c3nc(C(=O)Nc4cnn(C)c4[C@@H]4CC[C@@H](N)[C@H](F)CO4)ccc3F)c(F)c2)COC1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(3-methoxyoxetan-3-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 202. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.32 (dd, J=8.7, 4.0 Hz, 1H), 8.17 (t, J=8.9 Hz, 1H), 7.94 (s, 1H), 7.42 (d, J=9.3 Hz, 2H), 4.87-4.75 (m, 5H), 4.17 (ddt, J=49.0, 6.1, 2.6 Hz, 1H), 4.03-3.84 (m, 2H), 3.75 (s, 3H), 3.14 (s, 3H), 3.12-2.98 (m, 1H), 2.11-2.00 (m, 1H), 1.80-1.57 (m, 3H). LCMS (ES+) m/z 550 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:28][NH2:29]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:29][CH3:28])=[N:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN
Reactant: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Product: CNC(=Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-[3-(2,6-dichlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (2.0 g, 0.0045 mol), yellow mercuric oxide (1.18 g, 0.0054 mol) and 33% w/w methylamine in methylated spirit (40 ml) was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 1.53 g (78%), m.p. 153°-156 ° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:11]1[CH:12]=[C:13]([S:17][CH2:18][CH2:19][OH:20])[CH:14]=[CH:15][CH:16]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl.C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:11]1[CH:12]=[C:13]([S:17][CH2:18][CH2:19][O:20][S:30]([CH3:29])(=[O:32])=[O:31])[CH:14]=[CH:15][CH:16]=1
Reactant: CN1CCC(OC(c2cccc(SCCO)c2)c2nc3ccccc3s2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(OC(c2cccc(SCCOS(C)(=O)=O)c2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethanol (400 mg) in dichloromethane (5 mL) is added methanesulfonylchloride (1.25 molar equivalent) in dichloromethane (1.5 mL) and triethylamine (1.5 molar equivalent). The reaction mixture is stirred overnight at room temperature. Volatiles are removed under reduced pressure to dryness. Water is added and the aqueous phase is extracted by diethylether. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (dichloromethane/methanol from 98/2) to afford methanesulfonic acid 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl ester that will be used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11](OC)=[O:12])[CH:3]=1.P(Br)(Br)(Br)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:11](=[O:12])[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][N:8]=[C:4]2[CH:3]=1
Reactant: COC(=O)C(=CNc1cc(Br)ccn1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: O=P(Br)(Br)Br
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cnc2cc(Br)ccn2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mixture of dimethyl 2-((4-bromopyridin-2-ylamino)methylene)malonate (4.8 g, 15.2 mmol, 1 equiv) and POBr3 (16.1 g, 56.1 mmol, 3.7 equiv) was stirred at 80° C. for 2 h. After it was cooled to room temperature, the reaction mixture was poured into water carefully. Then the solution was adjusted pH to 8 with aq. Na2CO3 and extracted with DCM (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 3.4 g of the desired product. MS (ESI): 283, 285 (MH+).
Reaction SMILES: C(O[C@H]1C2C(=CC(Br)=CC=2)[C@@H](NC[C@@H](O)[C@@H](N)CC2C=C(F)C=C(F)C=2)C1)C=C.Br[C:31]1[CH:32]=[CH:33][C:34]2[C@H:35]3[CH2:52][C@@H:49]([C:50]=2[CH:51]=1)[NH:48][CH2:47][C@@H:46]([OH:53])[C@H:45]([CH2:54][C:55]1[CH:60]=[C:59]([F:61])[CH:58]=[C:57]([F:62])[CH:56]=1)[NH:44][C:43](=[O:63])[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38][CH2:37][O:36]3.[CH3:64][N:65]1[CH2:72][CH:71]2[CH:67]([CH2:68][NH:69][CH2:70]2)[CH2:66]1>>[F:62][C:57]1[CH:56]=[C:55]([CH:60]=[C:59]([F:61])[CH:58]=1)[CH2:54][C@@H:45]1[NH:44][C:43](=[O:63])[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38][CH2:37][O:36][C@@H:35]2[CH2:52][C@@H:49]([C:50]3[CH:51]=[C:31]([N:69]4[CH2:70][CH:71]5[CH:67]([CH2:66][N:65]([CH3:64])[CH2:72]5)[CH2:68]4)[CH:32]=[CH:33][C:34]=32)[NH:48][CH2:47][C@H:46]1[OH:53]
Reactant: O=C1CCCC=CCO[C@@H]2C[C@H](NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)N1)c1cc(Br)ccc12
Reactant: CN1CC2CNCC2C1
Agent: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(Br)ccc21
Product: CN1CC2CN(c3ccc4c(c3)[C@@H]3C[C@H]4OCC=CCCCC(=O)N[C@@H](Cc4cc(F)cc(F)c4)[C@H](O)CN3)CC2C1
Yield: 46 %

Procedure:
Step FG (1): The title compound (80 mg) was prepared in 46% yield via Ullman type coupling of (1S,4R,5S,15R)-19-bromo-5-(3,5-difluoro-benzyl)-4-hydroxy-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-7-one (TFA salt of Example 68) and 2-methyloctahydropyrrolo[3,4-c]pyrrole by following a procedure analogous to Step FF (1). LC/MS (M+H)+ 581.43. 1H NMR (400 MHz, CD3OD) δ ppm 1.27 (s, 2H) 1.49 (s, 1H) 1.98-2.06 (m, 2H) 2.23-2.35 (m, 5H) 2.38 (s, 2H) 2.54 (s, 1H) 2.58-2.69 (m, 2H) 2.75 (s, 1H) 2.92 (d, J=12.09 Hz, 4H) 2.99-3.11 (m, 2H) 3.18 (s, 1H) 3.55 (d, J=10.83 Hz, 1H) 3.83 (m, 2H) 3.88-3.98 (m, 2H) 4.05 (d, J=14.10 Hz, 1H) 4.30 (m, 1H) 4.65 (m, 1H) 5.42-5.54 (m, 2H) 6.70-6.77 (m, 5H) 7.19 (t, J=7.43 Hz, 2H). CD3OD
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]
Reactant: N#Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-1-fluoro-4-nitrobenzene (3.7 g) and 3-hydroxybenzonitrile (2.5 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (4.4 g), and the mixture was stirred at 60° C. for 4 hrs. After the completion of the reaction, water (50 mL) was added, and the mixture was stirred for 10 min. The resultant pale-yellow solid was collected by filtration, washed with diisopropyl ether, and dried to give the title compound (5.3 g) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1

Procedure:
Reacting 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 14.0 mg (0.10 mMol) 4-methylbenzoic acid at 70° C., 12.0 mg (69%) of the title compound were recovered.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7]C(=O)C)[CH2:3][CH2:2]1.[OH-].[K+].Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCO>[CH2:18]([O:17][C:15](=[O:16])[C:14]([CH3:21])([S:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH3:20])[CH3:19]
Reactant: CC(=O)SC1CCOCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC1CCOCC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
A solution of 153 g (0.96 mol) of thioacetic acid S-(tetrahydro-pyran-4-yl) ester in EtOH (3.5 L) is degassed with nitrogen over 0.5 h and 125 g (2.23 mol) of KOH are added. Then a solution of 250 mL (1.68 mol) of ethyl α-bromoisobutyrate in EtOH (1 L) are added over 0.5 h, during which the temperature increased to 40° C. The reaction is stirred for 18 h at RT under a nitrogen atmosphere. The reaction mixture is filtered, the solid is washed with EtOH (0.5 L) and the filtrate is concentrated under reduced pressure. The crude material is dryloaded onto silica and purified by dry-flash column chromatography (silica, eluent: nheptanes, 2-10% EE) to afford 158 g of 2-methyl-2-(tetrahydro-pyran-4-ylsulfanyl)-propionic acid ethyl ester. Yield: 71%; ESI-MS: 233 [M+H]+
Reaction SMILES: O=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@@H:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH:35]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[CH2:35]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@@H:4]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:3]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)[C@H]1CC(=O)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate of step 1n (850 mg) in toluene (10 mL) was added dropwise a solution of Ph3P═CH2 (0.25M in toluene/THF (3:1), 9.1 mL) at −10° C. The mixture was stirred and allowed to warm to RT during a period of 2 h. The mixture was diluted with ethyl acetate (75 mL) and washed with brine (3×25 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was flash chromatographed on silica gel column to afford 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-methylenepiperidine-1,2,3-tricarboxylate (546 mg). MS (ESI): 488.1 (M+Na+); 366.1 (M+H+−COO(t-Bu)).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([N:14]1[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccccc1)N1CCC(O)CC1
Temperature: 5 °C
Yield: 89.8 %

Procedure:
In this reference example, 7.03 g of benzoyl chloride was added dropwise to a mixture of 5.05 g of 4-hydroxypiperidine, 6.36 g of sodium carbonate and 60 ml of water at 10° C. with stirring. After the addition, the mixture was maintained at 5° C. for 2 hours. The reaction mixture was filtered, and then filtrate was extracted with dichloromethane. The extract was concentrated, and ether was added to crystallize, whereby 9.20 g of 1-benzoyl-4-hydroxypiperidine was obtained (yield: 90.1%).
Reaction SMILES: [CH:1](=[CH:10][C:11]([OH:13])=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O>>[CH:1](=[CH:10][C:11]([Cl:16])=[O:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=CC=Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C=CC=Cc1ccccc1
Temperature: 45 °C

Procedure:
Cinnamylidene acetyl chloride was prepared by stirring approximately 17.15 gms of cinnamylidene acetic acid with 30 ml thionyl chloride in 300 ml of petroleum ether for 12 hours at room temperature. The reaction mixture was then refluxed for 4 hours in an oil bath at a temperature of approximately 40 to 50° C. The excess thionyl chloride and the petroleum ether were removed under reduced pressure. 1HNMR: 3=6.2 ppm (d, 2H), δ=6.9 ppm (q, 2H), δ=7.5 ppm (m, 5H). UV (in dichloromethane): λmax=333 nm, λmin=256 nm.
Reaction SMILES: Br[C:2]1(Br)[CH2:16][CH2:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]1=[O:17].C1CCN2C(=NCCC2)CC1>C1COCC1>[OH:17][C:3]1[C:4]2[S:8][C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])=[N:6][C:5]=2[CH:15]=[CH:16][CH:2]=1
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)C(Br)(Br)CC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cccc(O)c2s1
Temperature: 20 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a suspension of 1-(6-bromo-7-oxo-4,5,6,7-tetrahydro-2-benzothiazolyl)-3-ethyl-urea 5 (0.100 g, 0.314 mmol) in THF (1.0 mL) was added DBU (0.141 mL, 0.94 mmol, 3 eq) dropwise at about 20° C. A dark green suspension was obtained while heat was generated upon addition of DBU. It was stirred at about 20° C. for about 18 hours. The reaction mixture was concentrated and dissolved in DMF (2 mL). LC/MS purification gave 0.024 g (32%) of the desired compound 8. 1H NMR (DMSO) δ 10.54 (br s, 1H, NH), 7.17–7.07 (m, 2H, ArH), 6.63 (d, 1H, J=6.9 Hz, ArH), 6.70 (br s, 1H, NH), 3.18 (m, 2H, CH2), 1.09 (t, 3H, J=7.2 Hz, CH3). LC/MS 238 (MH+); RP-HPLC RT 2.26 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@@H:8]([NH:10][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41])[CH3:9]
Reactant: C[C@H](N)c1ccncc1Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccncc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-chloropyridin-4-yl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 538/539/540 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=1>CN(C=O)C>[NH2:24][C:20]1[N:21]=[C:22]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[C:6]([C:11]([OH:14])([CH3:12])[CH3:13])=[N:7]2)[CH:23]=[CH:18][N:19]=1
Reactant: CC(C)(O)c1n[nH]c2cc(Br)ccc12
Reactant: Nc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(6-bromo-1H-indazol-3-yl)propan-2-ol (317 mg, 1.24 mmol) in DMF (10 mL) was added NaH (60% oil dispersion, 79.5 mg, 1.99 mmol) at 0° C. The reaction mixture was stirred at RT for 20 minutes before addition of 4-chloropyrimidin-2-amine (321.95 mg, 2.49 mmol). The mixture was stirred at RT for 10 minutes and then at 65° C. for 23 hr. The reaction mixture was quenched by addition of water (10 mL) and EtOAc (2 mL) was added. The resultant precipitate was collected by suction filtration and then thoroughly dried under high vacuum and triturated from diethyl ether. The crude product was purified by flash chromatography (Biotage, 1-5% methanol in DCM) to give the title intermediate as a pale yellow solid: 1H NMR (500 MHz, DMSO) delta 1.63 (6 H, s), 5.59 (1H, s), 7.23-6.93 (3H, m), 7.49 (1H, dd, J=8.6, 1.5 Hz), 8.07 (1H, d, J=8.6 Hz), 8.27 (1H, d, J=5.5 Hz), 9.11 (1H, d, J=1.4 Hz); LC-MS m/z=+347.95/349.80 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[C:20](=[O:28])[N:19]([CH3:29])[C:18]2=[O:30])[CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C.[O:40]=[C:41]1[CH2:46][O:45][C:44]2[CH:47]=[CH:48][C:49]([CH:51]=O)=[N:50][C:43]=2[NH:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:27][C:24]1[CH:25]=[C:26]2[C:21]([C:20](=[O:28])[N:19]([CH3:29])[C:18](=[O:30])[N:17]2[CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([NH:8][CH2:51][C:49]3[CH:48]=[CH:47][C:44]4[O:45][CH2:46][C:41](=[O:40])[NH:42][C:43]=4[N:50]=3)[CH2:14][CH2:13]2)=[CH:22][CH:23]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: Cn1c(=O)c2ccc(F)cc2n(CCN2CCC(N)CC2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)c2ccc(F)cc2n(CCN2CCC(NCc3ccc4c(n3)NC(=O)CO4)CC2)c1=O
Yield: 20.9 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoro-3-methylquinazoline-2,4(1H,3H)-dione trifluoroacetate salt (Intermediate 134) (0.476 mmol, 380 mg crude) was converted to the free base with N,N-diisopropylethylamine (0.5 mL, 3.0 mmol) and reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (102 mg, 0.571 mmol) and sodium triacetoxy borohydride (222 mg, 1.05 mmol) as described for Example 55. The reaction was diluted with dichloromethane and water. The layers were separated. The aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over magnesium sulfate and evaporated at reduced pressure. Chromatography on silica gel using methanol in dichloromethane (0-9%) with 1% concentrated ammonium hydroxide (aqueous) gave the product as a waxy material. This material was taken up in dichloromethane and washed well with water. The organic phase was dried over magnesium sulfate and evaporated to obtain the title compound as a colorless solid (48 mg, 21%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: O=[N+]([O-])c1cccc(COCCOCCCCCCBr)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Reaction time: 0.67 h
Yield: 101.8 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (4.40 g) in anhydrous DMF (75 ml) was treated under nitrogen at 0° with sodium hydride (60% dispersion in mineral oil, 1.04 g) and the mixture stirred for 40 min. A solution of 1-[(2-[(6-bromohexyl)oxy]ethoxy)methyl]-3-nitrobenzene (8.12 g) in DMF (10 ml) was added and the mixture stirred at 20° for 2 h. Phosphate buffer (pH 6.5, 100 ml) and water (100 ml) were added and the product extracted with EtOAc (4×100 ml). The combined organic layer was washed with water (3×100 ml) and dried (Na2SO4). The solvent was removed in vacuo to give a residue that was purified by Biotage. Elution with EtOAc-PE (1:1 then 3:2) followed by solvent evaporation in vacuo gave the title compound (9.50 g). LCMS RT=3.75 min, ES+ve 529 (MH)+.