Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[C:12]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.Cl[Pd]Cl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[CH:18]=[C:13]3[C:12]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(Br)cnc21
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(-c3cccs3)cnc21
Yield: 78 %

Procedure:
A mixture of bromide 30 (40.3 mg, 0.1 mmol), tributylthiophen-2-yl-stannane (62 μL, ca 0.2 mmol), PdCl2.(MeCN)2 (3.6 mg, 0.014 mmol), and tri-o-tolyl-phosphane (6.6 mg, 0.022 mmol) in toluene (0.9 mL) was stirred under N2 for 2 h. The reaction mixture was cooled and separated by PTLC with CH2Cl2 as eluent to afford 33 (31.7 mg, 78%) as yellowish solid. 1H NMR (400 MHz; CDCl3) δ 6.71 (dd, J=2.0, 1.0 Hz, 1H), 7.12 (dd, J=5.1, 3.6 Hz, 1H), 7.32 (dd, J=3.6, 1.2 Hz, 1H), 7.35 (dd, J=5.1, 1.2 Hz, 1H), 7.48-7.63 (m, 4H), 7.82 (m, 1H), 7.84 (s, 1H), 8.09 (d, J=2.2 Hz, 1H), 8.22-8.26 (m, 2H), 8.73 (d, J=2.2 Hz, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:34])([F:33])[C:22]1[C:30]([CH2:31][OH:32])=[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]2[N:23]=1.[CH2:35]([N:42]1[CH2:47][CH2:46][N:45]([C@@H:48]([CH2:53][NH:54][C:55](=[O:63])[C:56]2[CH:61]=[CH:60][C:59](O)=[CH:58][CH:57]=2)[C:49]([O:51][CH3:52])=[O:50])[CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:35]([N:42]1[CH2:43][CH2:44][N:45]([C@@H:48]([CH2:53][NH:54][C:55](=[O:63])[C:56]2[CH:57]=[CH:58][C:59]([O:32][CH2:31][C:30]3[C:22]([C:21]([F:20])([F:33])[F:34])=[N:23][N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=34)=[CH:60][CH:61]=2)[C:49]([O:51][CH3:52])=[O:50])[CH2:46][CH2:47]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(Cc2ccccc2)CC1
Reactant: OCc1c(C(F)(F)F)nn2ccccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCc2c(C(F)(F)F)nn3ccccc23)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
795 mg (3.0 mmol) of triphenylphosphine and 565 mg (2.6 mmol) of (2-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl)methanol are added respectively to a solution of 800 mg (2.0 mmol) of methyl (S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzoylamino)propanoate (prepared as described in example 22-5) in 8 ml of tetrahydrofuran. After stirring at ambient temperature for 30 min, 595 μl (3.0 mmol) of diisopropyl azodicarboxylate are added and the medium is stirred for 18 h at ambient temperature. After evaporating to dryness, the crude residue obtained is purified by chromatography over a silica column eluted with 100% ethyl acetate. 590 mg (49%) of methyl (S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-a]pyridin-3-ylmethoxy)-benzoylamino]propanoate are obtained in the form of a light-yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19]CC)=O)[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][NH2:25]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]([NH:24][NH2:25])=[O:19])[CH2:14][CH2:15]2)=[CH:22][CH:23]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc(C(C)(C)C)cc2)CC1
Solvent: CCO
Product: CC(C)(C)c1ccc(CN2CCN(CC(=O)NN)CC2)cc1

Procedure:
Synthesized according to General Procedure C: 6{20} (4.12 g, 12.9 mmol, 1 equiv.), anhydrous hydrazine (1.2 mL, 38.8 mmol, 3 equiv.), ethanol (26.0 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{20} (3.36 g, 84%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 8.17 (br s, 1H), 7.31 (d, 2H, J=8.5 Hz), 7.20 (d, 2H, J=8.5 Hz), 3.85 (br s, 2H), 3.46 (s, 2H), 3.05 (s, 2H), 2.52 (br s, 4H), 2.45 (br s, 4H), 1.30 (s, 9H). 13C-NMR (125 MHz, CDCl3): δ 170.4, 149.9, 134.5, 128.7, 125.0, 62.4, 60.5, 53.5, 52.9, 34.3, 31.3.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[N:10]1)(C)(C)C.Cl>C(O)C.Cl>[N+:14]([C:11]1[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc([N+](=O)[O-])n1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccn(CCO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
A solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-nitro-1H-pyrazole (prepared as in US 20080021032 Example 67, 6.34 g, 23.36 mmol) in ethanol (100 mL) was treated with concentrated hydrochloric acid (12 drops) and stirred for 1 h at room temperature. After this time, another portion of concentrated hydrochloric acid was added (12 drops) and it was stirred overnight at room temperature. After this time, the reaction mixture was concentrated in vacuo and then azeotroped with acetonitrile. The crude material was then purified by flash column chromatography (silica gel 60, 230-400 mesh, 80% ethyl acetate/hexanes) to afford 2-(3-nitro-pyrazol-1-yl)-ethanol (2.36 g, 94%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 8.00 (d, J=2.56 Hz, 1H), 7.03 (d, J=2.56 Hz, 1H), 5.00 (t, J=5.31 Hz, 1H), 4.26 (t, J=5.31 Hz, 2H), 3.77 (q, J=5.49 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[H-].[Na+].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>CN(C=O)C>[CH3:13][O:12][C:10]([C:7]1[S:6][C:5]2[CH:14]=[CH:15][C:2]([O:1][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH2:28][C:19]4[CH:20]=[CH:21][C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:18]=4)[CH:31]=3)=[CH:3][C:4]=2[C:8]=1[CH3:9])=[O:11]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: COC(=O)c1sc2ccc(O)cc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 5-hydroxy-3-methyl-benzo(b)thiophene-2-carboxylate (878.6 mg, 3.96 mmol) in dry DMF (20 ml) at room temperature is added sodium hydride (158 mg, 3.95 mmol) as a 60% dispersion in mineral oil. After 30 minutes of stirring 3-(2-quinolinylmethoxy)benzyl chloride (1.02 g, 3.60 mmol) is added. The solution is stirred at room temperature for 4 hours and quenched with ice-water. Extraction with ethyl acetate, washing with aqueous sodium carbonate, water and brine is followed by drying (MgSO4) and concentration. The residue is subjected to flash chromatography on silica gel. Elution with 25% ether in hexane affords methyl-3-methyl-5-[3-(2-quinolinylmethoxy)benzyloxy]benzo(b) -thiophene-2-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([OH:18])[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([OH:18])[C:11]4[CH:12]=[CH:13][CH:14]=[N:15][C:16]=4[CH:17]=3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Oc1nc(-c2ccc(Br)cc2)cc2ncccc12
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(-c3cc4ncccc4c(O)n3)cc2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a suspension of 7-(4-bromophenyl)-[1,6]-naphthyridin-5-ol (0.135 g, 0.45 mmol)) in DMF (4 mL), was added tetrakis(triphenylphosphine)palladium (0.025 g, 0.02 mmol). After 15 minutes, 4-methoxyphenylboronic acid (0.090 g, 0.60 mmol) and sodium carbonate (2 M aqueous solution, 0.5 mL, 1 mmol) was added. The mixture was heated to 100° C. for 12 hours and then cooled to room temperature. The white solid was collected by filtration and washed with water to afford the title compound (0.110 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:33]=[C:34]1[NH:38][CH:37]([CH2:39][CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]1>ClCCl.CN(C)C1C=CN=CC=1>[O:42]=[C:41]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([O:3][CH3:2])=[O:10])[CH2:40][CH2:39][CH:37]1[CH2:36][CH2:35][C:34](=[O:33])[NH:38]1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CCC1CCC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)CCC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.0 g (0.03 mol) L-proline methyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 4.42 ml (0.032 mol) triethylamine is added dropwise over a ten minute period. The mixture is stirred 15 minutes and a mixture of the following is added in a single addition: 6.85 g (0.033 mol) of dicyclohexylcarbodiimide; 200 mg (0.0016 mol) of 4-dimethylaminopyridine; 4.71 g (0.03 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 24 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 12:1 dichloromethanemethanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 60° C. yields 1-[1-oxo-3-(5-oxo-2-pyrrolidinyl)propyl]-L-proline, methyl ester as an analytically pure oil (0.55 hydrate) with the following characteristic proton NMR spectrum: 1H-NMR (CDCL3) 1.6-2.5 (m, 14H), 3.4-3.85 (m, 2H), 3. (s, 3H), 4.5 (m, 1H), 6.37 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([N:8]1[CH2:13][CH2:12][CH:11](C2OC3C=CC=CC=3C=2)[CH2:10][CH2:9]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[O:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:38]1[O:37][C:41]2[CH:24]=[CH:25][CH:3]=[CH:4][C:40]=2[CH:39]=1
Reactant: C1CCOC1
Reactant: COc1cc(C(=O)N2CCC(c3cc4ccccc4o3)CC2)cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: COc1cc(CN2CCCCC2c2cc3ccccc3o2)cc(OC)c1OC

Procedure:
A solution of 27.6 g of 1-(3,4,5-trimethoxybenzoyl)-4-(2-benzofuranyl)-piperidine in 150 ml of tetrahydrofuran is added dropwise to a refluxing solution of 4.0 g of lithium aluminium hydride in 120 ml of tetrahydrofuran. After 4 hours' refluxing, the reaction mixture is cooled, and the excess lithium aluminium hydride decomposed at -10° by means of 4 ml of water. The reaction solution is filtered off under suction, the filter residue then washed with 1 liter of chloroform, and the combined filtrates concentrated in vacuo. The residue is dissolved in 500 ml of 10% aqueous methanesulphonic acid, and the acid solution washed with ether. The aqueous phase is thereupon adjusted to pH 12 by addition of 30% sodium hydroxide solution, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered, and concentrated by evaporation to obtain crude 1-(3,4,5-trimethoxybenzyl)-2-(2-benzofuranyl)-piperidine. The hydrochloride is prepared with hydrogen chloride in ethyl acetate, and recrystallised from ethyl acetate, whereupon it melts at 212°.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[O:15])[CH:5]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:3]1=2.[C:23]([Mg]Br)#[CH:24]>C1COCC1>[CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([OH:15])[C:23]#[CH:24])[CH:5]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:3]1=2
Reactant: C#C[Mg]Br
Reactant: CCOCCOc1cc(C=O)cc2c1C(C)(C)CCC2(C)C
Solvent: C1CCOC1
Product: C#CC(O)c1cc(OCCOCC)c2c(c1)C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 97 %

Procedure:
40 g (131 mmol) of 5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde are dissolved in 400 mL of THF. 290 mL (145 mmol) of 0.5N ethynylmagnesium bromide solution are added and the reaction medium is then stirred for 1 hour. After treatment with 1N hydrochloric acid solution and extraction with ethyl acetate, followed by evaporation, the residue is purified by chromatography on a column of silica (eluent: 8/2 heptane/EtOAC). A yellow oil is obtained (m=42 g; yield=97%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].[CH3:8][O:9][C:10]1[CH:21]=[CH:20][C:13](/[CH:14]=[CH:15]/[C:16](OC)=[O:17])=[CH:12][CH:11]=1>CO>[CH3:8][O:9][C:10]1[CH:21]=[CH:20][C:13]([CH:14]2[S:5][CH2:4][CH2:3][NH:2][C:16](=[O:17])[CH2:15]2)=[CH:12][CH:11]=1
Reactant: COC(=O)/C=C/c1ccc(OC)cc1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2CC(=O)NCCS2)cc1
Temperature: 0 °C
Reaction time: 120 h

Procedure:
A mixture of 2-aminoethanethiol hydrochloride (31.0 g, 0.273 mol) and 140 mL of methanol is cooled to 0° C. and treated with pulverized sodium hydroxide (12.0 g, 0.475 mol) followed by trans-methyl 4-methoxycinnamate (52.4 g, 0.273 mol). The reaction mixture is allowed to warm to room temperature and stirred for 5 days. The mixture is then heated to 60° C. for 30 minutes and filtered while still warm. The methanolic solution is concentrated to ca 1/4 volume and the product is isolated by filtration (35 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13]3(OC(SC)=S)[CH2:16][O:15][CH2:14]3)[N:10]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][O:15][CH2:16]3)[N:10]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CSC(=S)OC1(c2cc(-n3c(C)ccc3C)nn2COCC[Si](C)(C)C)COC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cc(C2COC2)n(COCC[Si](C)(C)C)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
Into a 2 L round-bottom flask under nitrogen was placed a solution of ([3-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-yl]oxetan-3-yl]oxy)(methylsulfanyl)methanethione (97.0 g, 213.8 mmol, 1.0 equiv.) in toluene (1.2 L), tributyltin hydride (74.7 g, 256.7 mmol, 1.2 equiv.), and AIBN (7.0 g, 42.6 mmol, 0.2 equiv.). The resulting solution was stirred at 120° C. for 3 h, cooled to 30° C. and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/PE (1:100-1:5) to afford 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(oxetan-3-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole (30.0 g, 38% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]COC)=[CH:14][CH:15]=2)[C:10]([CH2:21][NH:22][CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)(C)C.C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH2:21][NH:22][CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc2c(c1)c(CNCc1cc(F)cc(F)c1)c(C(C)C)n2Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)c1c(CNCc2cc(F)cc(F)c2)c2cc(O)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indol-3-yl)-N-(3,5-difluorobenzyl)methanamine (Compound 5, 117 mg, 0.25 mmol) in isopropanol (2.0 ml) and THF (2.0 ml) was added 6 M HCl (0.4 ml). The mixture was stirred at room temperature for 16 h, and concentrated under vacuum. The mixture was diluted with EtOAc, and washed with phosphate buffer (pH=7.2), and brine, and dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 20-60% EtOAc-hexanes to yield 1-benzyl-3-((3,5-difluorobenzylamino)methyl)-2-isopropyl-1H-indol-5-ol (Compound 6) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])C)=[C:4]([CH3:11])[CH:3]=1.II.[OH-:14].[Na+].Cl>N1C=CC=CC=1.CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:14])=[C:4]([CH3:11])[CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: [OH-]
Agent: Cl
Agent: II
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1cc(O)ccc1C(=O)O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4'-Hydroxy-2'-methylacetophenone (15 gm, 0.1 mol) was dissolved in pyridine and iodine (25.4 gm) was added. This mixture was heated to 100° C. for 1 hr and then allowed to stand at room temperature overnight. A thick precipitate was obtained and the mixture was diluted with Et2O before filtering. The solid so obtained was added to 5N NaOH (200 ml) and heated on the steam bath for 1 hr before being cooled and acidified with HCl. This mixture was extracted twice with Et2O and the pooled organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was crystallized from Et2O-hexane to give 9.8 gm of the title compound as a solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].C1COCC1>>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])=[N:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4nnc(C(C)(C)C)s4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4nnc(C(C)(C)C)s4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 93.2 %

Procedure:
Using a procedure analogous to Example A1, 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.345 g, 0.672 mmol) and 2.00M MeNH2/THF (3.36 ml, 6.72 mmol) were combined to afford 1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.311 g, 93% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.822-7.75 (m, 3H), 7.69 (s, 1H), 7.39-7.37 (m, 1H), 7.34-7.30 (m, 1H), 7.16 (d, J=12.0 Hz, 1H), 2.90 (brd, J=4.8 Hz, 3H), 2.35 (s, 3H), 2.09 (s, 3H), 1.34 (s, 9H); MS (ESI) m/z: 497.0 (M+H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1OC)=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:45][O:46]C1C=C(C=CC=1)CN>>[Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([O:46][CH3:45])[CH:32]=1)=[O:24])=[CH:17]2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2cc3cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(O)c(CO)c4)ccc3[nH]2)c1

Procedure:
Prepared analogously to 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-methoxybenzyl)-1H-indole-2-carboxamide using 3-methoxybenzylamine to give the title compound as a pale brown foam.
Reaction SMILES: Br.[F:2][CH:3]([F:20])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16][C:17](=N)[NH2:18].[OH-].[Na+].O.ClC1[CH2:29][C:28]([CH3:31])([CH3:30])[O:27]N=1>C(O)C>[F:2][CH:3]([F:20])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16][C:17]1[CH2:29][C:28]([CH3:31])([CH3:30])[O:27][N:18]=1
Reactant: Cn1nc(C(F)(F)F)c(CSC(=N)N)c1OC(F)F
Reactant: CC1(C)CC(Cl)=NO1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 1.93 g (5.00 mmol) of 2-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethyl)-isothiourea hydrobromide in 10 ml of ethanol were added 0.48 g (12.00 mmol) of sodium hydroxide and 10 ml of -water, followed by 30 minutes of stirring at room temperature. Thereto was added 0.67 g (5.00 mmol) of 3-chloro-5,5-dimethyl-2-isoxazoline at room temperature, followed by further 12 hours of stirring under refluxing. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. The obtained residue was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1.02 g (yield: 56.7%) of 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline.
Reaction SMILES: CN1CCN([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N:13]3[N:17]=[N:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14]3)[CH:8]=2)C1=O.[Br:25]C1C=CC(N)=CC=1.N1C=CC=CC=1C=O>>[Br:25][C:12]1[CH:11]=[CH:10][C:9]([N:13]2[N:17]=[N:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14]2)=[CH:8][CH:7]=1
Reactant: CN1CCN(c2cccc(-n3nnc(-c4ccccn4)n3)c2)C1=O
Reactant: Nc1ccc(Br)cc1
Agent: O=Cc1ccccn1
Product: Brc1ccc(-n2nnc(-c3ccccn3)n2)cc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 1-methyl-3-[3-(5-pyridin-2-yl-2H-tetrazol- 2-yl)phenyl]imidazolidin-2-one, but using 4-bromoaniline (17.2 g, 100 mmol) and pyridine-2-carboxaldehyde (10.7 g, 100 mmol), 2-[2-(4-bromophenyl)-2H-tetrazol-5-yl]pyridine was obtained as an orange solid. 1H-NMR (CDCl3, 300 MHz) δ 8.83 (d, 1H), 8.33 (d, 1H), 8.15 (d, 2H), 7.96-7.87 (m, 1H), 7.70 (d, 2H), 7.44 (dd, 1H).