Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[N:59]1([CH2:65][CH2:66][OH:67])[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C.O>[OH:67][CH2:66][CH2:65][N:59]1[CH2:64][CH2:63][N:62]([C:25]([C:24]2[CH:23]=[CH:22][C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)=[O:26])[CH2:61][CH2:60]1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1)N1CCN(CCO)CC1
Reaction time: 12 h
Yield: 14.3 %

Procedure:
To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1 ml), HOBT (0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and triethylamine (0.16 ml, 1.17 mmol) were added and stirred for 5 min. (2-(piperazin-1-yl)ethanol (0.046 g, 0.353 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.025 g, 13%). M.P.: 158-160° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (d, J=2.7 Hz, 1H), 8.67 (d, J=8.7 Hz, 1H), 8.38 (d, J=7.8 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 8.17 (d, J=8.8 Hz, 1H), 8.02 (t, J=4.2 Hz, 2H), 7.83 (dd, J=8.7, 1.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.52 (dd, J=8.3, 4.2 Hz, 1H), 6.21 (s, 2H), 4.44 (t, J=5.3 Hz, 1H), 3.62 (m, 2H), 3.51 (q, J=6.0 Hz, 2H), 2.42 (m, 8H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:18]#[N:19])[C:13](=O)[NH:14][C:15]=3[CH3:16])[CH:7]=[CH:6][C:5]=12.P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:13]1[C:12]([C:18]#[N:19])=[CH:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=2)=[C:15]([CH3:16])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C#N)cc1-c1ccc2nccn2c1

Procedure:
A mixture of 3.1 g of 1,2-dihydro-5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-2-oxo-3-pyridinecarbonitrile, 30 ml of phosphorous oxychloride and 5 drops of dimethylformamide was stirred under reflux for 2 hours. An excess of phosphorous oxychloride was removed by distillation under reduced pressure and upon cooling, chloroform, a 20% NaOH solution and then an aqueous sodium carbonate solution were added to the residue to render it alkaline. The organic layer was taken by fractionation. After the chloroform layer was dried over magnesium sulfate, chloroform was removed by distillation. The residue was purified by column chromatography to obtain 1.9 g of 2-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-3-pyridinecarbonitrile.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:19]2[C:23]3=[N:24][CH:25]=[C:26]([C:28]4[N:29]=[N:30][N:31]([CH2:33][C:34](OCC)=[O:35])[CH:32]=4)[CH:27]=[C:22]3[N:21]=[CH:20]2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)(=[O:3])[CH3:2].[NH3:39]>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:19]2[C:23]3=[N:24][CH:25]=[C:26]([C:28]4[N:29]=[N:30][N:31]([CH2:33][C:34]([NH2:39])=[O:35])[CH:32]=4)[CH:27]=[C:22]3[N:21]=[CH:20]2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CCOC(=O)Cn1cc(-c2cnc3c(c2)ncn3-c2cc(NC(C)=O)cc(-c3ccc(F)cc3F)c2)nn1
Solvent: CO
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC(N)=O)nn4)cnc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
To a mixture of the compound of Example 270 (100 mg, 0.19 mmol) in methanol was added methonalic ammonia at 0° C. and the mixture was stirred at RT for 16 h. The mixture was distilled completely and the crude product was purified by preparative HPLC to give the product in 13% yield (12 mg). δ 10.5 (s, 1H) 9.14-8.97 (d, 2H), 8.82 (s, 1H), 8.76 (d, 1H), 8.35 (s, 1H), 7.89 (d, 1H), 7.81-7.80 (m, 2H), 7.65-7.55 (m, 1H), 7.27 (m, 1H), 5.55 (s, 2H), 2.8 (s, 2H), 2.10 (s, 3H); LC-MS (ESI): Calculated mass: 515.5; Observed mass: 516.5 [M+H]+ (rt: 1.37 min).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)=[C:5]([Br:7])[N:6]=1.C[Sn](C)(C)[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=1.[Cl-].[Li+]>O1CCOCC1.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.[Cu]I>[Br:7][C:5]1[N:6]=[C:2]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)[S:3][C:4]=1[C:8]1[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(Br)nc2Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2nc(Br)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Temperature: 25 °C
Yield: 12.1 %

Procedure:
The mixture of 3-(2,4-dibromo-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (1.10 g, 2.50 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (0.896 g, 3.00 mmol), tetrakis(triphenylphosphine)palladium (0) (0.155 g, 0.125 mmol), copper(I) iodide (0.143 g, 0.750 mmol) and lithium chloride (0.318 g, 7.50 mmol) in dry 1,4-dioxane (100 mL) was sonicated for 2 min, degassed and backfilled with nitrogen 5 times. The mixture was heated under nitrogen atmosphere to reflux for 90 min, then cooled to room temperature, filtered through celite and washed with dioxane/DCM. The filtrate was evaporated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel eluting with MeOH/DCM (0/100 to 5/95) to give a product, which was further purified on a silica column using MeOH/EtOAc/hexane (0/0/100 to 5/45/50) to give pure product (0.150 g, 13%). LCMS: (FA) ES+ 495, 497. 1H NMR (400 MHz, CDCl3) δ: 8.72 (s, 1H), 8.37 (m, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 7.68 (m, 1H), 5.57 (s, 2H), 3.73 (t, J=8.28 Hz, 2H), 2.25 (s, 3H), 0.97 (t, J=8.28 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9]1.B(F)(F)F.CCOCC.Cl>O1CCCC1.O>[NH:13]1[CH2:14][CH2:15][C:10]2([C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][O:9]2)[CH2:11][CH2:12]1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: Cl
Agent: FB(F)F
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: c1ccc2c(c1)COC21CCNCC1
Temperature: 0 °C
Yield: 79.1 %

Procedure:
A solution of lithium aluminum hydride (7.5 mL 1M in ether) diluted with 35 mL of tetrahydrofuran was cooled to 0° C. and added to a suspension of 3-oxospiro[isobenzofuran-1(3H),4'-piperidine] (0.38 g) in 40 mL of anhydrous tetrahydrofuran containing boron trifluoride etherate (6.9 mL). The reaction mixture was allowed to warm to room temperature and then refluxed for 3 hours. At the end of this period, the reaction mixture was cooled in ice and treated with 5% HCl (8 mL) followed by water (8 mL). After concentrating under reduced pressure, the reaction mixture was treated with concentrated HCl (8 mL) and heated to reflux, cooled to room temperature, the pH was adjusted to 5 by adding sodium hydroxide solution and extracted with ether. The aqueous layer was made basic (pH 11) with sodium hydroxide and extracted with two portions of dichloromethane. The dichloromethane layer was dried and evaporated to afford the named product (0.28 g) which was used in the next step without further purification; MS: 190; NMR: 7-1.1.9 (m, 4), 2.9-3.1 (m, 4), 5.1 (s, 2), 7.1-7.3 (m, 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.N([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1.[OH-].[Na+]>O.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:20]3[C:21](=[O:25])[CH2:22][CH2:23][CH2:24][C:19]=3[NH:9]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Solvent: O
Product: COc1ccc2c3c([nH]c2c1)CCCC3=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
To a chilled mixture of m-anisidine (10 g, 81 mmol) in water (200 mL) and concentrated hydrochloric acid (25 mL) is added sodium nitrite (5.6 g, 81 mmol) dissolved in water (30 mL). The mixture is stirred at 5° C. for one h. To this is added tin (II) chloride dihydrate (36.6 g, 162 mmol) dissolved in concentrated hydrochloric acid (75 mL). The mixture is allowed to warm to room temperature and stirred for 1 h. 1,3 cyclohexanedione (9.1 g, 81 mmol) is added and the mixture stirred for 2 h. The mixture is slowly neutralized with 10% NaOH. Filtered solids and washed with water (500 mL). The solids are then slurried in acetonitrile (600 mL), filtered and washed with acetonitrile (200 mL). The filtrates are dried over anhydrous sodium sulfate, filtered and concentrated. The residue is refluxed in TFA (70 mL) for 18 h. The mixture is partitioned between water and CH2Cl2. The organic layer is separated and washed twice with water (200 mL). The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated. Ethyl acetate (100 mL) is added to the residue and the solids filtered to give 2.29 g (13%) of the title compound; IR (drift) 3156, 3118, 3073, 1620, 1583, 1501, 1470, 1451, 1288, 1196, 1178, 1153, 1142, 1107, 830 cm−1. 1H NMR (DMSO-d6) δ2.08, 2.7, 2.9, 3.8, 6.7, 6.9, 7.8; Anal. Calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 60.95; H, 5.18; N, 5.61.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[O:18][CH3:19])=[O:4].O.[Li+].[OH-]>C1COCC1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[C:6]([O:18][CH3:19])[CH:7]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(Cl)cc2)ccc1C(=O)O
Yield: 91 %

Procedure:
To a solution of 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester, 30, (0.615 g, 2.22 mmol) in THF (20 mL) and H2O (5 mL) is added LiOH (0.932 g, 22.2 mmol). The resulting suspension is heated to reflux for 2 hours. The reaction is cooled and concentrated under reduced pressure. The crude product is acidified using conc. HCl and the resulting solid is collected by filtration, washed with H2O to afford 0.532 g (91% yield) of the desired compound as a grey solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.69 (1H, br s), 8.26 (1H, d, J=8.1 Hz), 7.53-7.58 (2H, m), 7.44-7.50 (2H, m), 7.33 (1H, dd, J=8.1, 1.6 Hz), 7.20 (1H, d, J=1.3 Hz), 4.17 (3H, s). HPLC-MS: m/z 263 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[OH-].[Na+].Cl[CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C(OCC)C.CO>C(O)C.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(-c2ccc(O)cc2)cc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: C=CCc1ccc(-c2ccc(OCC(O)CCc3cccnc3)cc2)cc1
Yield: 13.2 %

Procedure:
A solution of 4'-(2-propenyl)biphenyl4-ol (1.22 g; Biochemistry 1987, 26(18), 5908) in ethanol (10 ml) at room temperature was treated with a solution of sodium hydroxide (0.215 g) in water (5 ml) and was then heated at reflux. A solution of (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g) in ethanol (5 ml) was added to the latter and the resulting mixture heated at reflux for 2 hours. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethanol (95:5) to give a solid. Trituration with diethyl ether:methanol (9:1) gave the title compound as a colourless solid (0.256 g).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([CH3:12])[N:5]=1>CO>[Cl:3][C:4]1[N:5]=[C:6]([CH3:12])[C:7]([CH2:8][OH:9])=[CH:10][CH:11]=1
Reactant: Cc1nc(Cl)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(Cl)ccc1CO
Reaction time: 2 h

Procedure:
Sodium borohydride (0.73 g, 19.28 mmol) was added to a solution of 6-chloro-2-methylnicotinaldehyde (1.5 g, 9.64 mmol) in methanol (38.6 mL) at room temperature. The mixture was stirred for 2 hours, then quenched with water and saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:28][S:27](=[O:30])(=[O:29])[CH2:26][C:25]=2[CH:31]=1>C(O)(C)C>[O:29]=[S:27]1(=[O:30])[CH2:26][C:25]2[CH:31]=[C:21]([NH:20][C:14](=[O:16])[C:13]([N:10]3[CH2:9][CH2:8][CH:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)=[O:17])[CH:22]=[CH:23][C:24]=2[NH:28]1
Reactant: Cc1ccc(CC2CCN(C(=O)C(=O)O)CC2)cc1
Reactant: Nc1ccc2c(c1)CS(=O)(=O)N2
Solvent: CC(C)O
Product: Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4c(c3)CS(=O)(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from [4-(4-methyl-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 119b) and 5-amino-1,3-dihydro-2,1-benzisothiazole-2,2-dioxide according to the method described in Example 94. Melting Point: 186° C. (isopropanol)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]3)[N:28]=2)=[CH:19]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: O[C@H]1CC[C@H](Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1

Procedure:
Using the procedure of example 1, trans-4-amino-cyclohexanol (200 mg) was reacted with compound 1f (100 mg) to provide compound 18 (18 mg, 22%). 1H NMR (400 MHz, CD3OD) δ 8.95 (d, J=8.0 Hz, 1H), 8.28 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 8.13 (d, J=5.6 Hz, 1H), 7.26 (dd, J=8.0 Hz, 4.8. Hz, 1H), 7.02 (d, J=5.2 Hz, 1H), 3.91 (m, 1H), 3.65 (m, 1H), 2.17 (m, 2H), 2.05 (m, 2H), 1.45 (m, 4H). MS (ESI) m/z: 310 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: NCCCc1ccc(CO)cc1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCCc1ccc(CO)cc1)c1ccc(-c2ccccn2)cc1

Procedure:
Palladium on carbon (5%, 0.15 g) was added to a solution of 4-(3-benzyloxycarbonylaminopropyl)benzylalcohol (1.00 g), which is the product of Reference example 50(a) in ethanol (20 ml). The mixture was stirred under an atmosphere of hydrogen at ambient temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to afford 4-(3-aminopropyl)benzylalcohol as a gum. In a similar manner to that described in Example 5, a reaction was carried out using 4-(3-aminopropyl)benzylalcohol, 4-pyridine-2-ylbenzoic acid (668 mg) and carbonyidiimidazole (650 mg) and the reaction mixture was treated to afford the desired compound (0.74 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-:25])=[O:24])=[C:6]([CH:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:9](C(OC)=O)[C:10]([O:12][CH3:13])=[O:11])[CH:7]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([N+:42]([O-:44])=[O:43])=[C:31]([CH:33]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][C:35]([OH:37])=[O:36])[CH:32]=1.[Cl-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-:25])=[O:24])=[C:6]([CH:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([N+:42]([O-:44])=[O:43])=[C:31]([CH:33]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][C:35]([OH:37])=[O:36])[CH:32]=1
Reactant: COC(=O)CC(c1cc(Cl)ccc1[N+](=O)[O-])C(C(=O)OC)C(=O)OC
Agent: O=C(O)CC(CC(=O)O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CC(CC(=O)OC)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Variant B: Adapting literature known protocols (Krapcho, Synthesis, 1982, 805-822 & 893-914; and Stowe, et al., Org. Lett., 2010, 12(4), 756-759), a solution of trimethyl 2-(5-chloro-2-nitro-phenyl)propane-1,1,3-tricarboxylate (18b′) (3.74 g, 10.0 mol) and sodium chloride (NaCl) (292 mg, 5.0 mmol) in a mixture of dimethylsulfoxide (DMSO) (23 mL) and water (780 μL) is heated to reflux for about 12 h. The reaction is monitored by TLC and/or analytical LC/MS to completion. Aqueous work-up and purification by silica gel column chromatography using ethyl acetate (EtOAc) and hexanes mixtures afford dimethyl 3-(5-chloro-2-nitro-phenyl)pentanedioate (18b″). Adapting literature known protocols (Nejman, et al., Tetrahedron, 2005, 61, 8536-854), 3-(5-chloro-2-nitro-phenyl)pentanedioic acid (18b) is prepared heating a solution of dimethyl 3-(5-chloro-2-nitro-phenyl)pentanedioate (18b″) (3.16 g, 10.0 mmol) in a mixture of 6.0 M hydrochloric acid (HCl) and 1,4-dioxane for about 12 h to reflux (105° C. oil bath temperature) to effect complete ester hydrolysis and decarboxylation. The reaction is monitored by TLC and/or analytical LC/MS to completion. The solvents are distilled off under reduced pressure using a rotary evaporator. Aqueous work-up and purification by crystallization from ethyl acetate (EtOAc) and hexanes mixtures afford the title compound (18b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:23][P:24](=[O:41])([O:33]CC2C=CC=CC=2)[O:25]CC2C=CC=CC=2)[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:23][P:24](=[O:25])([OH:33])[OH:41])[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=P(CN(c1ccc2ccccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=P(O)(O)CN(c1ccc2ccccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1

Procedure:
72 mg dibenzyl {[(3,5-dichloro-phenylsulphonyl)-naphthalen-2-yl-amino]-methyl}-phosphonate in 6 ml of methanol are hydrogenated in the presence of 3 mg palladium on activated charcoal (10% Pd). The catalyst is filtered through kieselguhr and the filtrate is evaporated down in vacuo. The flask residue is stirred with diisopropylether, suction filtered and dried.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13](Br)[N:14]=2)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[C:25]([SiH2:29][O:30][C:31]([CH3:56])([CH3:55])[C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[N:36]=[C:35]2[Sn](CCCC)(CCCC)CCCC)([CH3:28])([CH3:27])[CH3:26]>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.[Cu]I>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:35]3[C:34]4[C:38](=[CH:39][CH:40]=[C:32]([C:31]([CH3:56])([CH3:55])[O:30][SiH2:29][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:33]=4)[N:37]([CH3:41])[N:36]=3)[N:14]=2)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C(C)(C)O[SiH2]C(C)(C)C)cc34)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (300 mg, 0.73 mmol) and 5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-tributylstannanyl-1H-indazole (Example 273, 665 mg, 0.82 mmol) were dissolved in DMF (4.8 ml). The reaction mixture was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (42 mg, 0.036 mmol) and copper (I) iodide (28 mg, 0.147 mmol) were added. The reaction mixture was stirred at 80° C. overnight then cooled to room temperature, quenched with water and diluted with petroleum ether. The resulting suspension was filtered and the solids washed with water, petroleum ether and a minimal amount of diethyl ether then dried under high vacuum to afford 426 mg (92%) of 2-[5-(tert-butyldimethyl-silanyloxymethyl)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a brown powder.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=4[CH:16]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2nc[nH]c2n1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a stirred solution of 5-bromo-3H-imidazo[4,5-b]pyridine (1 g, 5.05 mmol) from Step 2 of this Example in anhydrous DMF (25 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 222 mg 5.56 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.39 g, 6.06 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was allowed to warm to rt and stirred for a further 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM, followed by 1% MeOH in DCM to afford 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.02 g, 52%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.96 (d, J=0.9 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.43 (dd, J=1.5, 8.3 Hz, 1H), 5.60 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 391 and 393 (M+H)+.