Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18](O)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=2)=[N:6]1.P(Cl)(Cl)([Cl:30])=O.O.C(=O)([O-])O.[Na+]>S1(CCCC1)(=O)=O>[Cl:30][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=3[F:1])[N:6]=2)[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=[N+]([O-])c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1Cl
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
109.00 g (249.95 mmol) of the compound from example 78A were initially charged in sulfolane (490 ml), then 55.92 ml (599.88 mmol) of phosphoryl chloride were added and the mixture was heated to 120° C. for 1 h. After cooling, the mixture was added cautiously to water (3 l) and stirred for 15 min. Sodium hydrogencarbonate was added in portions until the pH was 6. The precipitate formed was filtered off with suction and washed with water. The residue was stirred with 200 ml of dichloromethane/methanol (v/v=4:1) for 30 min, filtered off with suction, washed with dichloromethane, acetone and petroleum ether and dried under high vacuum. This gave 63.00 g (62% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[N:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.Cl.Cl.[CH3:32][C:33]1([CH3:42])[CH2:38][NH:37][CH2:36][C:35]2[CH:39]=[N:40][NH:41][C:34]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:32][C:33]1([CH3:42])[CH2:38][N:37]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[N:21]=2)=[O:27])[CH2:36][C:35]2[CH:39]=[N:40][NH:41][C:34]1=2
Reactant: CC1(C)CNCc2cn[nH]c21
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)O)n3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)N4Cc5cn[nH]c5C(C)(C)C4)n3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.11 g (0.26 mmol) 4-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-[1,3,5]triazine-2-carboxylic acid, 59 mg (0.26 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride and 0.15 mL (1.1 mmol) TEA were placed in 1.5 mL DMF. 93 mg (0.29 mmol) TBTU were added and the reaction mixture was stirred for three days at RT. The substance was purified by HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:15].Cl.[CH:17]([CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:52]([N:55]2[C:59]([C:60]([F:63])([F:62])[F:61])=[N:58][N:57]=[N:56]2)=[CH:51][C:48]=1[CH:49]=O>ClCCl.C(O)(=O)C>[ClH:15].[ClH:15].[CH:17]([CH:30]1[NH:31][CH2:32][CH2:33][N:34]([CH2:49][C:48]2[CH:51]=[C:52]([N:55]3[C:59]([C:60]([F:63])([F:62])[F:61])=[N:58][N:57]=[N:56]3)[CH:53]=[CH:54][C:47]=2[O:46][CH3:45])[CH2:35]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C=O
Reactant: c1ccc(C(c2ccccc2)C2CNCCN2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1CCNC(C(c2ccccc2)c2ccccc2)C1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Sodium triacetoxyborohydride (127 mg) was added portionwise to a mixture of 2-benzhydrylpiperazine dihydrochloride (97.6 mg), N,N-diisopropylethylamine (0.104 ml) and 2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]benzaldehyde (61.2 mg) in a mixture of dichloromethane (5 ml) and acetic acid (1 drop) at 0° C. and the whole was stirred at 5° C.˜room temperature overnight. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (70:1). The fractions containing the objective compound were collected, evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give 3-benzhydryl-1-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]piperazine dihydrochloride (74 mg) as a colorless powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C(OC(C1CC(C(OCC)=O)=C(C)NC=1C)=O)C>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 210 °C
Yield: 16.8 %

Procedure:
3.9 g (11 mmole) 5-(4-[2-(4-cyanophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione and 3.88 g (15 mmole) diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate were mixed and heated to 210° C. under vacuum for 1 hour. The solid material was dissolved in ethyl acetate, evaporated in vacuo, purified by chromatography on silica gel with first dichloromethane, then dichloromethane:diethyl ether (95:5) and finally dichloromethane:methanol (95:5) as eluents. Crystallization in acetone/water gave 0.65 g (yield 17%) of the desired product.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[NH2:20][CH:21]1[CH:26]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH:25]2[CH2:34][CH2:35][CH:22]1[CH2:23][CH2:24]2.CN(C)C=O.C(O)(C)C>C(N(CC)CC)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:26]2[CH:21]([NH:20][C:2]3[C:3]4[N:4]=[CH:5][N:6]([C:7]=4[N:8]=[CH:9][N:10]=3)[C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[CH:22]3[CH2:35][CH2:34][CH:25]2[CH2:24][CH2:23]3)=[CH:32][CH:31]=1
Reactant: NC1C2CCC(CC2)C1c1ccc(Cl)cc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4C5CCC(CC5)C4c4ccc(Cl)cc4)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 96 h

Procedure:
A mixture of 28.6 g of 6-chloro-9(β-D-ribofuranosyl)-purine, 23.6 g of 2-amino-3-p-chlorophenylbicyclo[2,2,2]octane, 450 ml of dimethylformamide, 450 ml of isopropanol and 50 ml of triethylamine is left to stand at 20° for 4 days. The mixture is evaporated, the residue is dissolved in chloroform, the chloroform solution is washed with 1% aqueous acetic acid and evaporated again and the residue is triturated with ether to give N6 -[2-(4-chlorophenyl)-bicyclo[2,2,2]oct-3-yl]-adenosine (Ia). M.p.: 145° (decomposition). Rf: 0.41 (silica gel; CH2Cl2 :CH3OH 9:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[N:13][C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([C:8]2[N:6]3[CH:7]=[C:2]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:12]=[N:13][C:14]=1[O:19][CH3:20]
Reactant: C1COCCN1
Reactant: COc1cc(-c2cnc3ccc(Br)cn23)cnc1OC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(-c2cnc3ccc(N4CCOCC4)cn23)cnc1OC
Temperature: 100 °C
Yield: 19.6 %

Procedure:
To a 5 mL microwave tube was added 6-bromo-3-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-a]pyridine (0.050 g, 0.15 mmol), morpholine (0.020 g, 0.22 mmol), 2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene (0.0028 g, 0.0045 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.0014 g, 0.0015 mmol), sodium tert-butoxide (0.020 g, 0.21 mmol), and toluene (3 mL). The resulting reaction mixture was sealed and heated to 100° C. in closed system for 6 h. The reaction was cooled and the solvent was removed. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, 12 g SiO2, DCM:MeOH=96%:4%, Flow=30 mL/min). The product fractions were collected. The solvent was removed in vacuo to afford the desired product as white solid (10.0 mg). MS (ESI pos. ion) m/z: 341.0. Calcd exact mass for C18H20N4O3: 340.2. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.99-3.09 (m, 4H) 3.84-3.92 (m, 4H) 3.94 (s, 3H) 4.11 (s, 3H) 7.12 (d, J=9.79 Hz, 1H) 7.17 (s, 1H) 7.57-7.65 (m, 3H) 7.96 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]([O:16]CC)=[O:15])=[CH:7]2.C1COCC1.O.[OH-].[Li+:28]>C1COCC1>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]([O-:16])=[O:15])=[CH:7]2.[Li+:28]
Reactant: CCOC(=O)Cc1cc2cc(OC(F)(F)F)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])Cc1cc2cc(OC(F)(F)F)ccc2[nH]1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
A solution of ethyl 2-(5-(trifluoromethoxy)-1H-indol-2-yl)acetate (96 mg, 0.33 mmol) in 2:1 THF/water (6 mL) was treated with lithium hydroxide (10 mg, 0.4 mmol), and the reaction was stirred overnight. The THF was stripped, and the aqueous was freeze-dried to yield 90 mg of an off-white solid as product.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][C@@H:9]([NH2:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:21][C:22]=1I)=[O:17].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:21][C:22]=1[NH:11][C@@H:9]([CH3:10])[CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:13])[CH3:12])=[O:17]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1I
Reactant: C[C@H](N)CCO[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N[C@@H](C)CCO[Si](C)(C)C(C)(C)C
Reaction time: 16 h

Procedure:
An argon purged flask was charged with 3-(tert-butyl-dimethyl-silanoxy)-1-(S)-methylpropylamine (3.50 g, 17.24 mmol), 5-(3,3-dimethyl-but-1ynyl)-3-iodo-thiophene-2-carboxylic acid methyl ester (3.0 g, 8.62 mmol), Pd(OAc)2 (288 mg, 1.29 mmol), and ±-BINAP 801 mg, 1.29 mmol). Argon degassed toluene (90 mL) was add to the reaction mixture and the reaction was placed in a preheated 120° C. oil bath and stirred for 16 h. The solvent was removed under reduced pressure and taken up in hexanes. 3-[3-(tert-butly-dimethyl-silanoxy)-1-(S)-methyl-propylamino]-5-(3,3-dimethyl-but-1-ynyl)thiophene-2-carboxylic acid methyl ester was isolated by silica gel chromatography (2.87 g, 79%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2OCOC[O:17]2)=[N:8][N:7]=1.[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[N:8][N:7]=1
Reactant: Cc1cccc(Nc2nnc(C3OCOCO3)c3ccccc23)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(Nc2nnc(C=O)c3ccccc23)c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
A suspension of 3.15 g (9.74 mmol) 1-(3-methylanilino)-4-([1,3,5]trioxan-2-yl)phthalazine in 150 ml H2SO4 (10% in H2O) is stirred for 7 h at 100° C. The suspension is cooled to RT and adjusted to alkaline pH with NaOH (20% in H2O), the title compound that precipitates out is filtered off and washed with water, 1H-NMR (DMSO-d6) 10.17 (s, HCO), 9.84 (s, HN), 9.02 (d, 1H), 8.67 (d, 1H), 8.03 (m, 2H), 7.8-7.6 (2 sb, 2H), 7.30 (t, 1H), 6.98 (d, 1H), 2.36 (s, 3H); FAB-MS (M−H)+=262.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])=O.Cl.[N:18]1([C:23](=[NH:25])[NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH3:15][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:3]1[NH:25][C:23]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:24][C:2]=1[CH3:16]
Reactant: COC(=O)c1ccc(C)c(C(=O)C(C)Br)c1
Reactant: N=C(N)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C)c(-c2[nH]c(N3CCCC3)nc2C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(2-bromopropanoyl)-4-methylbenzoate (compound 197.2, 500.0 mg, 1.75 mmol) in N,N-dimethylformamide (15 mL). Pyrrolidine-1-carboximidamide hydrochloride (compound 197.1, 260.8 mg, 1.75 mmol) was treated with K2CO3, then added to the reaction. The reaction mixture was stirred for 1 h at 50° C. The reaction mixture was diluted with 30 mL of H2O. The aqueous phase was extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with PE/EtOAc (1:1)˜EtOAc/methanol (15:1) as eluent to furnish 230.0 mg (44%) of the title compound as a dark blue solid.
Reaction SMILES: [ClH:1].[CH2:2]([N:5]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[H-].[Na+]>O.CN(C=O)C>[ClH:1].[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH2:20][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][N:5]([CH2:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH3:4])=[CH:13][CH:14]=1
Reactant: CCCN(CCC)CCCc1ccc(O)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)CCCc1ccc(OCc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a mixture of 4-[3-(N,N-dipropylamino)propyl]phenol hydrochloride (0.152 g), 2-bromomethylnaphthalene (0.165 g), and DMF (10 ml) was added potassium carbonate (0.131 g). Sodium hydride (60% oil dispersion: 0.044 g) was added to the reaction mixture under ice cooling and the reaction mixture was stirred at room temperature for one hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: hexane/ethyl acetate=4/1) and converted into its hydrochloride by 4 N hydrochloric acid/ethyl acetate solution followed by recrystallization from methanol/diisopropylether to obtain the titled compound (0.169 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:16]([OH:18])=O)[CH2:8]2.S(Cl)(Cl)=O.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl.O.C1(C)C=CC=CC=1>[O:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:30]=[CH:31][C:32]([NH:33][C:16]([CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]=4[O:2][CH3:1])[CH2:8]3)=[O:18])=[CH:34][CH:35]=2)[CH2:27][CH2:28]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1ccc([N+](=O)[O-])c2c1CCC(C(=O)O)C2
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c2c1CCC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.3 g, 5 mmol), toluene (20 mL) and thionyl chloride (1.8 mL, 25 mmol) was heated at 80° C. for 1 h. The solvents were removed in vacuo and the residue, dissolved in methylene chloride (10 mL), was added to a solution of 4-morpholinoaniline (890 mg, 5 mmol) and triethylamine (1.0 g, 10 mmol) in methylene chloride (20 mL) at 0° C. The mixture was stirred at 20° C. for 2 h, water was added and the precipitate was filtered to yield 1.9 g (90%) of the title product as crystals: mp 251-253° C.; EIMS (70 eV) m/z (relative intensity) 411 (100, M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>O1CCOCC1.O.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>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]3)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: O=[N+]([O-])c1ccc(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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCc2cc(-c3ccc([N+](=O)[O-])cc3)ccc2C1
Yield: 50.6 %

Procedure:
Pd(PPh3)4 (0.0736 g, 0.06 mmol) was added to a solution of 6-bromo-2-tetralone (1.5 g, 6.66 mmol) in 50 mL of 1,4 dioxane-H2O (3:1) mixture under argon atmosphere, followed by cesium carbonate (6.49 g, 19.99 mmol) and 4-nitrophenyl boronic acid (1.32 g, 7.99 mmol). The reaction mixture was degassed for 5 min. The reaction mixture was refluxed for 4 h and solvent removed under reduced pressure. The residue partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulphate, filtered and removed under reduced pressure. The product was purified by flash chromatography using 18% ethyl acetate in hexane to afford title compound (0.9 g, 50%) as solid. 1H NMR (300 MHz, CDCl3): 8.31 (d, J=9.0 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.5 (m, 2H), 7.27 (s, 1H), 3.66 (s, 2H), 3.16 (t, J=6.9 Hz, 2H), 2.61 (t, J=6.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])[CH:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]=1.[CH3:23]C(C)([O-])C.[K+].CCOC(C)=O>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:9])([CH3:12])([CH3:16])[CH3:23]
Reactant: CCCCCCC1C=C(Cl)C=CN1C(=O)Oc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCC1C=C(Cl)C=CN1C(=O)OC(C)(C)C
Temperature: -42 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-Chloro-1-(phenoxycarbonyl)-2-n-hexyl-1,2-dihydropyridine (7.42 g, 23.2 mmol) in 250 ml of THF at −42° C. was added dropwise over 15 minutes a 1.0M solution of potassium t-butoxide (93 mL, 92.87 mmol). The resulting orange solution was stirred for 1 h at −42° C. The cooling bath was removed, and the reaction mixture was allowed to stir for 20 min while being slowly warmed to room temperature. Water (50 ml) and ether (70 ml) were added and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with cold 1.0 N NaOH (2×35 ml), and brine. The organic phase was dried over MgSO4, filtered through Celite, and concentrated in vacuo to give the crude product. Column chromatography with 5% EtOAc in hexanes afforded 5.9 g (81% from previous reaction) as a clear colorless oil that was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 6.85-6.63 (dd, 1H), 5.55 (br s, 1H), 5.23-5.12 (m, 1H), 4.87-4.56 (m, 1H), 1.72-1.25 (m, 19H), 0.89-0.85 (t, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:21]=1>C(O)(CC)C>[N:1]1([C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=3)[CH:21]=2)[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccc(Nc2cc(-n3ccc4cccnc43)ncn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution of compound 7-azaindole (18 mg, 0.15 mmol) in sec-BuOH (5 mL) was added DIEA (0.20 mL) and the reaction mixture was stirred for 15 min at RT. 6-Chloro-N-(4-(trifluoromethoxy)phenyl)pyrimidin-4-amine (29 mg, 0.1 mmol) was then added and the temperature was raised to 90° C. and continued stirring for another 16 h. The solvent was removed and the title compound was purified by prep. HPLC (15 mg, 40% Yield). MS m/z 372.10 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](=[O:16])[NH:11][N:12]([CH3:15])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18]1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:37][C:38]1[N:39]=[C:40]([CH2:48]Cl)[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2.O>CN(C)C=O>[CH2:1]([N:5]1[C:9]2[C:10](=[O:16])[N:11]([CH2:48][C:40]3[C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:47]=[C:38]([CH3:37])[N:39]=3)[N:12]([CH3:15])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: Cc1cc2ccccc2c(CCl)n1
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(C)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(C)n(Cc3nc(C)cc4ccccc34)c(=O)c21
Temperature: 50 °C
Reaction time: 5 h

Procedure:
0.20 g of (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione and 0.10 g potassium carbonate are placed in 2 ml of dimethylformamide. Then 0.10 g of 3-methyl-isoquinolin-1-yl-methylchloride are added and the mixture is stirred for 5 h at 50° C. After the addition of water the mixture is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate, and the solvent is removed. The residue is purified over silica gel (cyclohexane/ethyl acetate 1:1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(C3CN(Cc4ccccc4)CCO3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(C2CNCCO2)cc1
Yield: 96.2 %

Procedure:
To a solution of 4-benzyl-2-(4-benzyloxy-phenyl)-morpholine (8.35 g; 23.2 mmol) in MeOH (100 mL) was added a catalytic amount of palladium hydroxide (0.65 g; ˜20 wt % on carbon, wet). The resulting mixture was treated with hydrogen (1 atm.) at RT, overnight. Subsequently, the mixture was filtered over kieselguhr, rinsed with MeOH, and concentrated in vacuo to afford 4-morpholin-2-yl-phenol (4.00 g), which was used as such.