Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]([C:23]#[N:24])([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[BH4-].[Na+]>O.O.O.O.O.O.[Co](Cl)Cl.CO>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:24][CH2:23]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)c(OC)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC1(c2ccc(OC)c(OC)c2)CNC(=O)C1
Temperature: 25 °C

Procedure:
Combined 3-cyano-3-(3,4-dimethoxy-phenyl)-pentanedioic acid diethyl ester (16.8 g, 48.0 mmol), methanol (300 mL) and cobalt (II) chloride hexahydrate (22.8 g, 96.0 mmol). Cooled until the internal temperature reached 10° C. Added portionwise so as to maintain the reaction temperature below 20° C., sodium borohydride (44.2 g, 1.17 mol). After addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirred over the weekend. Concentrated in vacuo to obtain a residue. Partitioned between 1N HCl (800 mL) and dichloromethane (800 mL). The organic layer was extracted with 1N HCl (2×200 mL). The combined aqueous layers were extracted with dichloromethane (3×100 mL). The organic layers were combined, dried over Na2 SO4, filtered, and concentrated in vacuo to obtain a residue. The residue was chromatographed on silica gel eluting with ethyl acetate/methanol (20:1) to obtain the title compound: Rf =0.27 (silica gel, 20:1 ethyl acetate/methanol), mp=116°-118° C. Analysis: calculated for C16H21NO5C 62.53; H 6.89; N 4.56; Found C 62.52; H 6.85; N 4.50.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:19])[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.Cl.[C:21](Cl)(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1.O>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]2[NH:19][C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:18][C:9]2=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(-c2ccncc2)c(-c2ccco2)nc1N
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: c1cncc(-c2nc3nc(-c4ccncc4)c(-c4ccco4)nc3[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.5 %

Procedure:
A mixture of 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 87, 146 mg, 0.58 mmol) and nicotinoyl chloride hydrochloride (516 mg, 2.9 mmol) in pyridine (5 mL) was stirred and heated at reflux for 24 h. Then polyphosphoric acid was added and the stirring was continued at the same temperature for 24 h. The reaction was allowed to cool to room temperature and was poured into water and extracted with ethyl acetate. The organic phase was dried (MgSO4), evaporated and the residue was purified by silica gel chromatography (CH2Cl2/MeOH/NH3 50:8:1). The appropriate fractions were concentrated to leave a solid which upon washing with diethyl ether give the title compound as a light brown solid (82 mg, 61%).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[O:25][CH:16]2[CH2:17][CH2:18][C:19]2[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:16]2=[O:25])=[CH:13][CH:14]=1
Reactant: COc1ccc(C23OC2CCc2ccccc23)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: COc1ccc(C2C(=O)CCc3ccccc32)cc1
Temperature: 80 °C

Procedure:
6.0 Grams (0.05 mols) of magnesium sulfate and 500 mL of toluene were added to 50.5 g (0.20 mols) of 7b-(4-methoxyphenyl)-1a,2,3,7b-tetrahydro-1-oxacyclopropa[a]naphthalene, and the mixture was heated at 80° C. for 2 hours. After cooled, the reaction product was washed two times each with 250 mL of water, and the organic layer was condensed under reduced pressure to obtain 1-(4-methoxyphenyl)-3,4-dihydro-1H-naphthalene-2-one represented by the following formula,
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14]1)[CH:7]=[CH:6]2)#[N:2].Cl.[OH:26][NH2:27].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.ClCCl>[OH:26][NH:27][C:1](=[NH:2])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:14]1)[CH:7]=[CH:6]2
Reactant: CC(C)(C)C(=O)NC1CCN(c2ccc3cc(C#N)ccc3n2)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)NC1CCN(c2ccc3cc(C(=N)NO)ccc3n2)C1
Temperature: 90 °C

Procedure:
A mixture of the product of Step D (60 mg; 0.1863 mmol), hydroxyl amine hydrochloride (3 eq.), sodium carbonate (4 eq.) in 1.5 mL water and 2.5 mL ethanol was heated to 90° C. for 6 h. The mixture was diluted with dichloromethane, washed twice with brine, dried over sodium sulfate, filtered through a fritted funnel and the volatiles were removed under vacuum. This provided the product, MS: m/z 356, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:13]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH:14]([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:21][CH2:22][N:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:18][CH2:19]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(C)CN1CCNCC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-isobutylpiperazine (0.078 g, 0.55 mmol) with the aid of isopropanol (5 ml) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.112 g, 63%). 1H-NMR (500 MHz, DMSO-d6) 0.87 (d, J=6.56 Hz, 6H, CH(CH3)2), 1.77 (m, 1H, CH(CH3)2), 2.08 (d, J=7.35 Hz, 2H, N—CH2), 2.47 (br s, 4H, piperazine N(CH2)2), 3.04 (br s, 4H, piperazine N(CH2)2), 6.96 (s, 2H, NH2), 8.15 (s, 1H, 6-H);
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.BrCCCOC1C=CC([C:31]2([C:37]#[N:38])CCOC[CH2:32]2)=CC=1.C([O-])([O-])=O.[K+].[K+].Cl.N1CCC1>C(#N)C>[N:38]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:37][CH2:31][CH2:32]1
Reactant: N#CC1(c2ccc(OCCCBr)cc2)CCOCC1
Reactant: N#CC1(c2ccc(OCCCCl)cc2)CCOCC1
Agent: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: N#CC1(c2ccc(OCCCN3CCC3)cc2)CCOCC1
Temperature: 40 °C
Yield: 57 %

Procedure:
A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile and 4-[4-(3-bromo-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile (7.5 g, 27 mmol), K2CO3 (9.6 g, 70 mmol) and azetidine hydrochloride (4.0 g, 43 mmol) in acetonitrile (80 mL) was heated at 40° C. for 18 hours. The mixture was concentrated in vacuo then partitioned between water (150 mL) and ethyl acetate (150 mL). The organic layer was extracted with 2M HCl solution (2×100 mL) and the combined acid layers basified with 40% potassium hydroxide solution, then extracted with DCM (2×150 mL). The DCM layers were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure to give the title compound (1.1 g, 57%) as a clear, viscous oil. 1H NMR (400 MHz, DMSO) δ 1.80 (quintet, 2H), 2.00-2.14 (m, 6H), 2.58 (t, 2H), 3.20 (t, 4H), 3.88 (m, 2H), 4.00-4.11 (m, 4H), 6.90 (d, 2H), 7.38 (d, 2H). LRMS (APCI+) m/z 301 (MH)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][N:7]=1)=[O:5])[CH3:2].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:45][CH2:44][CH2:43][C@@:30]3([C:34](=[O:35])[N:33]([C@H:36]4[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[CH2:29]2)=[C:24]([F:46])[CH:23]=1>>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:45][CH2:44][CH2:43][C@@:30]4([C:34](=[O:35])[N:33]([C@H:36]5[CH2:37][CH2:38][C@@H:39]([OH:42])[CH2:40][CH2:41]5)[CH2:32][CH2:31]4)[CH2:29]3)=[C:24]([F:46])[CH:23]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCN(c1ccc(Br)cc1F)C2
Product: CCNC(=O)c1ccc(-c2ccc(N3CCC[C@]4(CCN([C@H]5CC[C@@H](O)CC5)C4=O)C3)c(F)c2)cn1

Procedure:
This compound was prepared by using procedures that were analogous to those described for the synthesis of Example 1, Step 8 starting from N-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide and (5S)-7-(4-bromo-2-fluorophenyl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-on. LC/MS m/e 495.3 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:23][C:10]2[CH:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:9]=2[CH:8]=1.[CH3:24][S:25]SC>CCCCCC.O1CCCC1>[CH3:16][N:13]1[CH2:14][CH2:15][C:9]2[CH:8]=[C:7]([S:25][CH3:24])[S:23][C:10]=2[CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1
Reactant: CN1CCc2cc(Br)sc2C(c2ccccc2)C1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1cc2c(s1)C(c1ccccc1)CN(C)CC2
Temperature: 25 °C

Procedure:
A solution of n-butyl lithium in n-hexane (1.6M, 0.75 ml) was added dropwise to a stirred solution of 2-bromo-6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (0.40 g hydrobromide salt converted to free base by aqueous ammonia/dichloromethane extraction) in dry tetrahydrofuran (10 ml) cooled to -70° under nitrogen. After 10 minutes at -70° dimethyl disulphide (0.11 ml) was added dropwise and the mixture allowed to warm to room temperature. After 30 minutes the solution was evaporated, water (10 ml) added to the residue and extracted with dichloromethane (2×5 ml). The extracts were dried, filtered and evaporated to a pale yellow solid. Recrystallisation twice from n-hexane (4 ml) gave white needles (m.p. 90°) of the title product.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>C(O)C.[Fe]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnc(-c2ccccn2)nc1Nc1cc(C2CC2)[nH]n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cnc(-c2ccccn2)nc1Nc1cc(C2CC2)[nH]n1
Yield: 85229.3 %

Procedure:
A mixture of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitro-2-(pyridin-2-yl)pyrimidin-4-amine (1.29 g, 0.004 mmol, 1 equiv.) and Fe (2.24 g, 0.04 mmol, 10 equiv.) in ethanol and aqueous NH4Cl (2.12 g, 0.04 mmol, equiv.) was bubbled with N2, and refluxed for 1 h. Then, the reaction mixture was filtered. The liquid was evaporated to afford N4-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(pyridin-2-yl)pyrimidine-4,5-diamine (1.0 g, 85%). LC-MS (m/z)=294 [M+H]+.
Reaction SMILES: F[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17]([C:2]2[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ncccc1F
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: O=Cc1ncccc1S(=O)(=O)c1ccccc1

Procedure:
The title compound was prepared by the method of Preparation 5a using 3-fluoropyridine-2-carbaldehyde and benzene sulfinic acid sodium salt.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[S:3]([C:6]1[CH:33]=[CH:32][C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C@@H:27]([CH3:31])[CH2:28][O:29]C)[CH:25]=2)[C:14]([NH:16][C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[O:15])=[CH:8][CH:7]=1)(=[O:5])=[O:4].I[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:34][N:2]([CH3:1])[S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C@@H:27]([CH3:31])[CH2:28][OH:29])[CH:25]=2)[C:14]([NH:16][C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[O:15])=[CH:32][CH:33]=1)(=[O:4])=[O:5]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)C)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(=O)(=O)N(C)C)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.5 %

Procedure:
To a solution of 3-{4-[(dimethylamino)sulfonyl]phenoxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (500 mg, 1.0 mmol) in acetonitrile (30 mL) was added iodotrimethylsilane (0.73 mL, 1.0 g, 5.1 mmol) dropwise. The resulting mixture was stirred at RT for 20 hours. Aqueous sodium hydrogen carbonate solution (saturated, 5 mL) was added slowly and the resulting mixture was concentrated under reduced pressure. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL). The organic layers was washed with brine (50 mL), dried (MgSO4) and evaporated to afford the crude product. This was purified by flash chromatography (eluting with an increasing gradient of 60 to 100% ethyl acetate in isohexane) to afford the pure title compound (216 mg, 45%).
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10](C(O)=O)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:16]CCl.Cl>O1CCOCC1>[ClH:16].[CH:1]1([S:4]([N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)N1CCN(S(=O)(=O)C2CC2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(C1CC1)N1CCNCC1
Reaction time: 2.5 h

Procedure:
14.37 g of tert-butyl ester of 4-cyclopropanesulfonyl-piperazine-1-carboxylic acid is put in a 2-liter three-necked flask, under nitrogen atmosphere. 412 ml of dichloromethane is added. The reaction mixture is cooled in an ice bath and 4M hydrochloric acid in solution in dioxane is added dropwise. The reaction mixture is allowed to return gradually to room temperature. The reaction mixture is stirred for 2.5 h, then evaporated and concentrated. The residue is taken up in a small amount of ethyl ether, triturated and then filtered and dried. 10.25 g of 1-cyclopropanesulfonyl-piperazine hydrochloride is obtained in the form of a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[N:32]=[C:31](Cl)[C:30]([Cl:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:26][C:27]1[N:32]=[C:31]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:15]=[CH:16][CH:17]=3)=[O:10])[CH:5]=[CH:6][CH:7]=2)[C:30]([Cl:34])=[CH:29][N:28]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)Cc2cccc(N)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)Cc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of tert-butyl (3-{[(3-aminophenyl)acetyl]amino}phenyl)carbamate (0.31 g, 0.91 mmol) and 2,4,5-trichloropyrimidine (0.15 g, 0.82 mmol) in DMF (3 mL) was added potassium carbonate (0.14 g, 0.99 mmol). The resulting mixture was stirred overnight at rt. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous was extracted with EtOAc and the combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The crude mixture was purified by column chromatography to give the desired product (0.25 g, 62%). LCMS for C23H23Cl2N5O3 (M-tBu+H)+: m/z=432.0, 434.0. 1H NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.54 (s, 1H), 9.32 (s, 1H), 8.35 (s, 1H), 7.93 (s, 1H), 7.78 (t, J=2.1 Hz, 1H), 7.47 (s, 1H), 7.46 (m, 1H), 7.33 (dd, J=8.7, 7.5 Hz, 1H), 7.31 (m, 1H), 7.15 (m, 1H), 7.11 (t, J=8.0 Hz, 1H), 6.98 (m, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][CH2:19][C:9]2[N:7]3[CH:8]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]3=[N:11][C:10]=2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:23]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Product: Cc1cc(Cl)nc(NCc2c(-c3ccc(Cl)cc3)nc3ccc(Cl)cn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4-chloro-6-methylpyrimidin-2-amine. 1H-NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.55 (d, J=9.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 2H), 7.18 (dd, J=1.8, 9.5 Hz, 1H), 6.55 (s, 1H), 5.59 (broad, 1H), 4.99 (d, J=5.6 Hz, 2H), 2.34 (s, 3H); m/e+ 419 for C19H14Cl3N5 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[C:30]([N:40]2[CH:44]=[CH:43][C:42]([CH3:45])=[N:41]2)[CH:29]=1.C([O-])=O.[K+]>O.C(#N)C.C[Ir-4](Cl)(C)(C)(C)(C)C1C=CC=C1>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]([OH:39])[C:35]([F:38])([F:37])[F:36])=[C:30]([N:40]2[CH:44]=[CH:43][C:42]([CH3:45])=[N:41]2)[CH:29]=1
Reactant: Cc1ccn(-c2cc(Br)ccc2C(=O)C(F)(F)F)n1
Agent: C[Ir-4](C)(C)(C)(C)(Cl)C1C=CC=C1
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: O=C[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](O)C(F)(F)F)n1
Temperature: 50 °C

Procedure:
Pentamethylcyclopentadienyl iridium (III) chloride dimer (CAS#12354-84-6) (10.4 mg) and (1R,2R)-(−)-N-(4-toluene sulfonyl)-1,2-diphenyl ethylene diamine (CAS#144222-34-4) (9.2 mg) were combined in water (120 mL), then heated to 50° C. for 5 h to provide the “Iridium complex.” 1-[4-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanone (16 g, 48 mmol) was dissolved in acetonitrile (120 mL) to which the Iridium complex and potassium formate (3.1 g, 3.7 mmol) were added. The reaction mixture was heated to 50° C. for 8 h. The reaction mixture was then cooled to RT, partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Recrystallization from hot heptane (200 mL) provided the title compound.
Reaction SMILES: Cl[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[NH2:21][CH2:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.CCOCC>COCCOC>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:21][CH2:22][C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:8]=1
Reactant: NCc1cc2ccccc2[nH]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2F)=NC1Cl
Solvent: COCCOC
Solvent: CCOCC
Product: O=C1Nc2ccccc2C(c2ccccc2F)=NC1NCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-(RS)-Chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (150 mg, 0.520 mmol) and 2-aminomethylindole (75.9 mg, 0.520 mmol) were combined in 1,2-dimethoxyethane (3 ml) and the mixture stirred 20 min. at 25° C. The mixture was evaporated to dryness in vacuo and the residue treated with H2O and extracted with EtOAc (3x). The combined extracts were washed with H2O (1X), dried over MgSO4, filtered and stripped to dryness in vacuo to give an orange oil which, after chromatography on silica gel (4% MeOH in CH2Cl2) provided the title compound as a white solid from ether: (m.p. 200°-202°).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)CC[N:9]([C:19](C3C4C(=CC=CC=4)C=CC=3)=O)[CH2:8][C:7]=2[CH:31]=1.Cl.N1C=C(CN2[C:45]3[CH:46]=[CH:47][C:48]([C:50]#N)=[CH:49][C:44]=3[CH2:43][N:42]([S:52]([CH3:55])(=[O:54])=[O:53])[C@H](CC3C=CC=CC=3)C2)N=C1>>[ClH:1].[ClH:1].[NH:17]1[CH:18]=[C:14]([CH2:13][N:12]2[C:45]3[CH:46]=[CH:47][C:48]([C:50]4[CH:5]=[CH:4][CH:3]=[CH:31][CH:7]=4)=[CH:49][C:44]=3[CH2:43][N:42]([S:52]([CH3:55])(=[O:53])=[O:54])[C@H:5]([CH2:4][C:3]3[CH:19]=[N:9][CH:8]=[CH:7][CH:31]=3)[CH2:6]2)[N:15]=[CH:16]1
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Agent: Cl
Product: CS(=O)(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1cccnc1

Procedure:
Example 273 was prepared as a light yellow solid from D-pyridylalanine and Compound B of Example 226 using the following sequence: Compound C of Example 226; Compound D of Example 226; Compound B of Example 264; Compound C of Example 264.
Reaction SMILES: [I-:1].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1>CC(C)=O>[I:1][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
260 mg (1.73 mmol) of sodium iodide are added to a solution of 640 mg (1.16 mmol) of ethyl 4′-(3-bromopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 40 ml of acetone. The reaction mixture is stirred overnight at room temperature. The precipitate formed is filtered off and the filtrate is evaporated. 608 mg of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=118° C., yield=71%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=2)[CH:5]=1)([OH:3])=[O:2].C1C2C(=CC=CC=2)C=CC=1.S(Cl)([Cl:29])=O>>[C:14]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[C:10]=1[Cl:29])([OH:16])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Solvent: c1ccc2ccccc2c1
Product: O=C(O)c1ccc2c(Cl)c(C(=O)O)ccc2c1
Temperature: 80 °C

Procedure:
2,6-Dicarboxynaphthalene having carboxyl groups bonded to a naphthalene nucleus, designated compound A, is chosen as a starting compound. Two moles of thionyl chloride is added to one mole of compound A, and the mixture is heated to about 75 to 90° C., preferably about 80° C., with stirring in a nitrogen atmosphere. Then the stirring force is diminished, and the reaction mixture is refluxed for about 6 to 18 hours, desirably about 10 to 12 hours. The bath temperature is set at about 90 to 100° C., at which unreacted thionyl chloride is removed by evaporation over about 2 hours to obtain 2,6-dicarboxychloronaphthalene, designated compound B.