Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:64])[CH:7]([NH:13][C:14](=[O:63])[CH2:15][CH2:16][CH:17]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:55])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:23][CH2:22]1)=[O:20])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:78]1[C:83](=[O:84])[CH2:82][CH2:81][C:79]1=[O:80])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:80]=[C:79]1[CH2:81][CH2:82][C:83](=[O:84])[N:78]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][CH:7]([NH:13][C:14](=[O:63])[CH2:15][CH2:16][CH:17]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:55])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[CH2:23][CH2:22]1)=[O:20])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:64]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)NC(CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)NC(CCC(=O)ON2C(=O)CCC2=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Yield: 86.4 %

Procedure:
To a solution of 2-[4-tert-butoxycarbonyl-4-({4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]-cyclohexanecarbonyl}amino)butyrylamino]pentanedioic acid 1-tert-butyl ester (4.6 g) in THF (150 ml) was added TSTU (1.68 g). DIPEA (0.97 ml) was added. After stirring over night the mixture was concentrated in vacuo. The residue was crystallized from acetonitrile to afford the title compound as a solid (4.4 g, 87%)
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=2)[CH2:11]1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:11][CH:12]([O:14][C:15]2[CH:16]=[CH:17][C:18](=[O:21])[N:19]([CH3:24])[CH:20]=2)[CH2:13]1
Reactant: O=C([O-])[O-]
Reactant: O=c1ccc(OC2CN(c3cccc(CO)c3F)C2)c[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(OC2CN(c3cccc(CO)c3F)C2)ccc1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
5-({1-[2-Fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one (160 mg) was mixed with DMF (3 ml), and methyl iodide (114 mg) and potassium carbonate (200 mg) were added thereto, followed by stirring at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added CHCl3 and water. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)-1-methylpyridin-2(1H)-one (106 mg).
Reaction SMILES: [NH2:1][C:2]1[O:21][C:6]2[N:7]([CH3:20])[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13](OC)=[C:12](OC)[CH:11]=3)[C:5]=2[CH:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:3]=1[C:29]#[N:30].F[C:32]1[CH:39]=[CH:38]C(C=O)=[CH:34][CH:33]=1.C(#N)CC#N.C(N(CC)CC)C.COC1C=C(C2CC(=O)N(C)N=2)C=CC=1OC>C(O)C>[NH2:1][C:2]1[O:21][C:6]2[N:7]([C:20]3[CH:38]=[CH:39][CH:32]=[CH:33][CH:34]=3)[N:8]=[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:5]=2[CH:4]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:3]=1[C:29]#[N:30]
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(-c2nn(C)c3c2C(c2ccc(F)cc2)C(C#N)=C(N)O3)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)C2)cc1OC
Solvent: CCO
Solvent: N#CCC#N
Solvent: CCN(CC)CC
Product: N#CC1=C(N)Oc2c(c(-c3ccccc3)nn2-c2ccccc2)C1c1ccc(F)cc1
Reaction time: 0.02 h
Yield: 67 %

Procedure:
6-amino-3-(3,4-dimethoxyphenyl)-4-(4-fluorophenyl)-1-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile UC-E21: A mixture of 4-fluorobenzaldehyde (300 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 3-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrazol-5(4H)-one (672 mg, 2.87 mmol, 1 equ.). The precipitate formed was filtered out and washed with ethanol and hexanes, and re-crystallized from ethanol to give 6-amino-4-(4-fluorophenyl)-1,3-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (782 mg, 1.93 mmol, 67%) as a white powder. 1H-NMR (400 MHz) DMSO: 7.20-7.18 (m, 2H), 7.09-7.03 (m, 5H), 6.96-6.95 (d, 1H), 6.80-6.78 (d, 2H), 5.02 (s, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.62 (s, 3H) 13C-NMR (100 MHz) DMSO: 162.6, 159.0, 148.7, 146.0, 144.6, 141.0, 141.0, 129.8, 129.7, 125.9, 120.4, 119.0, 115.7, 115.4, 111.8, 109.8, 94.7, 55.8, 55.7, 37.3, 34.4; LC/MS-MS: 407.1→341.1 m/z; GS1 and GS2 at 30, DP=71, CE=33, CXP=22, tR=3.86 min.
Reaction SMILES: C1(C=CC2C=CC=CC=2)C=CC=CC=1.[C:15]1([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](C(C3C=CC=CC=3)=C)[CH:24]=2)=[CH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C(C2C=CC(C(C3C=CC=CC=3)=C)=CC=2)=C)C=CC=CC=1>>[C:15]1([C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=C(c1ccccc1)c1cccc(C(=C)c2ccccc2)c1
Agent: C(=Cc1ccccc1)c1ccccc1
Agent: C=C(c1ccccc1)c1ccc(C(=C)c2ccccc2)cc1
Product: C=C(c1ccccc1)c1ccccc1

Procedure:
For instance, in accordance with an embodiment of the present invention, a living macrocarbocation, e.g., living cationic polyisobutylene, is reacted with a double diphenylethylene, e.g., 1,3-bis(1-phenylethenyl)benzene (sometimes referred to as meta-double diphenylethylene) or 1,4-bis(1-phenylethenyl)benzene (sometimes referred to as para-double diphenylethylene), to produce a 1,1-diphenylethylene end-functionalized carbocationic polymer. The carbocation is then alkylated with a suitable alkylating agent, e.g., with an organometallic compound such as dimethylzinc, whereupon the resulting macromonomer is readily metallated with a suitable organometallic compound such as an alkyllithium compound, thereby providing a living anionic macroinitiator in near quantitative yield. A sterically hindered lithium compound, e.g., a 1,1-diphenylalkyllithium species, is used in certain embodiments to remove impurities that may be present alongside the 1,1-diphenylethylene end-functionalized polymer, thereby preventing premature termination of the living macroanion.
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]#[CH:27])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([C:22](=[O:23])[NH2:3])[CH2:25][C:26]#[CH:27])([CH3:16])([CH3:15])[CH3:14]
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22.1 %

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (563 mg, 2.94 mmol) was added to a solution of commercially available (S)-2-(tert-butyoxycarbonylaminopent-4-ynoic acid (e.g. Acros, 626 mg, 2.94 mmol) and 1-hydroxybenzotriazole (397 mg, 2.94 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred at 0° C. for 20 min. A 25% aqueous solution of ammonia (2.38 ml) was added. The reaction mixture was stirred for 16 h, while warming up to room temperature. It was diluted with ethyl acetate (150 ml) and washed with a 10% aqueous solution of sodium hydrogensulphate (150 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (250 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with a mixture of brine (75 ml) and water (75 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (50 g), using dichloromethane/methanol (10:1) as eluent, to give 138 mg of ((S)-1-carbamoylbut-3-ynyl)carbamic acid tert-butyl ester.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[C:17]1([CH2:23][CH2:24][CH:25]=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO.[Pd].[H][H]>[ClH:1].[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=CCCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@H](CO)NCCCc1ccccc1

Procedure:
L-Serine methyl ester hydrochloride (0.9 moles, 14 g), triethylamine (0.9 moles, 9.1 g) and 3-phenylpropionaldehyde (0.9 moles, 12.1 g) are dissolved in dry methanol (370 ml) in a Parr bottle and hydrogenated under 45 psi in the presence of 10% Pd/C, until the hydrogen absorption ceases.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[S:12])=[C:5]([CH3:38])[CH:4]=1.Br[CH2:40][C:41](OC)=[O:42]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:41](=[O:42])[CH2:40][S:12]/[C:11]/2=[N:13]/[N:14]=[CH:15]\[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:20][CH:21]=2)=[C:5]([CH3:38])[CH:4]=1
Reactant: COC(=O)CBr
Reactant: COc1cc(C)c(NC(=S)N/N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1
Solvent: O
Solvent: CCO
Product: COc1cc(C)c(N2C(=O)CS/C2=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1
Temperature: 70 °C
Yield: 76.1 %

Procedure:
To a solution of (E)-N-(4-methoxy-2,6-dimethylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazine-carbothioamide (250 mg, 0.462 mmol) in EtOH (5 mL) was added methyl bromoacetate (100 mg, 0.65 mmol), and the mixture was heated to 70° C. for 4 h. The mixture was allowed to cool to room temperature and diluted with water (1 mL). The precipitate was vacuum filtered, giving the title compound as a white solid (204 mg, 76%): mp 188-190° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.33 (s, 1H), 8.22 (d, J=8.1 Hz, 2H), 7.90-7.70 (m, 4H), 7.39 (d, J=8.7 Hz, 2H), 6.72 (s, 2H), 4.01 (s, 2H), 3.87-3.73 (s, 3H), 2.18 (s, 6H); ESIMS m/z 581 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:22]4[CH2:23][CH2:24][N:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:26][C:21]4=[N:20][C:14]=3[C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.ClCCl.[Pd]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]3[CH2:26][N:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24][CH2:23][N:22]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: CS(=O)(=O)N1CCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N1CCn2c(nc3c(N)nc4cc(O)ccc4c32)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.7 %

Procedure:
3-(Benzyloxy)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine, (3.34 g, 10.0 mmol) prepared as described in Example 368, was dissolved in a mixture of methanol (100 mL) and dichloromethane (100 mL) and transferred to a hydrogenation vessel charged with 10% palladium on carbon (5 g, 47 mmol). The vessel was placed under hydrogen pressure (50 psi, 3.45×105 Pa) and shaken for two days at ambient temperature. An analysis by LC/MS indicated the presence of starting material. The catalyst was removed by filtration through a layer of CELITE filter aid, and the filtrate was placed under hydrogen pressure (50 psi, 3.45×105 Pa) again for two days in the presence of 10% palladium on carbon (5 g, 47 mmol). The catalyst was removed by filtration through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure. The residue (560 mg) was combined with material from another run to provide 1.19 g of 6-amino-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-3-ol.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][OH:27])[CH:21]=[N:20][CH:19]=1>>[N:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][O:27][C:2]2[C:11]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:21]=[N:20][CH:19]=1
Reactant: OCCOc1cncnc1
Reactant: Clc1nc2ccccc2nc1N1CCNCC1
Product: c1ccc2nc(N3CCNCC3)c(OCCOc3cncnc3)nc2c1

Procedure:
The title compound was prepared according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)quinoxaline (0.66 g, 2.65 mmol; from Example 162, Step 1) and 2-(5-pyrimidinyloxy)ethanol (0.45 g, 3.20 mmol). Yield 0.55 g (59%); mp 115-117° C.; HRMS m/z calcd for C18H20N6O2 (M)+ 352.1648, found 352.1654. Anal. (C18H20N6O2) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: CCCCCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), amylamine (0.147 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.334 g, 66%): TOF MS ES+ 333.2 (M+H)+, HRMS calcd for C17H22N4O2F 333.1727 (M+H)+, found 333.1722, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.3 min, 96.8% purity.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.C1(C)C=CC=CC=1.C[O:29][C:30]([C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([CH3:39])[N:33]=1)=O>O1CCOCC1>[CH3:38][C:37]1[C:32]([C:30]([NH:15][C:13]2[CH:12]=[CH:11][N:10]3[CH:16]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[N:14]=2)=[O:29])=[N:33][C:34]([CH3:39])=[CH:35][CH:36]=1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: COC(=O)c1nc(C)ccc1C
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 43.7 %

Procedure:
To a white suspension of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 80 mg, 0.38 mmole) in dioxane (3 ml) is added at RT trimethyl aluminium sol. 2M in toluene (0.8 ml, 1.52 mmole, 4 eq.). The mixture is stirred for 45 min at RT. A solution of 3,6-dimethyl-pyridine-2-carboxylic acid methyl ester (63 mg, 0.38 mmole, 1 eq.) in dioxane (0.4 ml) is then added and the light brown solution is refluxed overnight. The brown solution is loaded on 2 g silica and purified by chromatography on a 12 g RediSep silica cartridge (eluent heptane/ethyl acetate 30-70% 15 min) affording 3,6-dimethyl-N-(2-phenylimidazo[1,2-a]pyrimidin-7-yl)picolinamide (57 mg, 43.6%) as a white solid. MS (m/e)=344.2 [M+H+].
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[NH2:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>O>[NH2:16][C:17]1[CH:22]=[C:21]([O:15][C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc(Cl)cc2)ccc1[N+](=O)[O-]

Procedure:
1.26 G. 57% sodium hydride in oil suspension in 20 ml. dimethylformamide is treated with 3.9 g. p-chlorophenol. When the mixture becomes homogenous, 2.5 g. 2-amino-4-chloro-1-nitrobenzene is added and the mixture heated for five hours at 130°-135° C. The crude product is obtained by diluting the reaction mixture with water and filtering and washing with water and hexane. Recrystallization from methanol gives pure 2-amino-4-(4-chlorophenoxy)-1-nitrobenzene.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:37]=2)[C:32]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[N:31]1.C([O-])([O-])=O.[K+].[K+].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.O>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:34]=[C:33]4[C:38](=[CH:37][CH:36]=3)[N:30]([CH3:29])[N:31]=[C:32]4[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1nc(-c2ccccn2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3ccccn3)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.207 mmol), 1-methyl-3-(pyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (83.3 mg, 0.25 mmol), Pd(PPh3)4 (24 mg, 21 mmol), and K2CO3 (86 mg, 0.62 mmol). De-gassed dioxane (2 mL) and water (0.5 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to rt, the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 40% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 9.21-9.15 (m, 1H), 8.84-8.77 (m, 1H), 8.25 (dd, J=8.8, 1.7 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.78 (td, J=7.7, 1.7 Hz, 1H), 7.59-7.49 (m, 4H), 7.47 (d, J=8.9 Hz, 1H), 7.29-7.24 (m, 1H), 5.21 (s, 1H), 4.17 (s, 3H), 3.75 (s, 3H), 2.59 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:6]=1.[CH3:12][C:13](C)([O-])[CH3:14].[K+].C(Br)C#C>O1CCOCC1>[CH2:14]([S:1][C:2]1[S:3][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:6]=1)[C:13]#[CH:12]
Reactant: Sc1nnc(-c2cccs2)s1
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: C1COCCO1
Product: C#CCSc1nnc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 g of 2-mercapto-5-thienyl-1,3,4-thiadiazole are placed in 40 ml of dioxan and stirred for 15 minutes with 3.36 g of potassium tert.-butoxide. Subsequently, 5.9 g of propargyl bromide are added dropwise at 30° C. and the reaction mixture is stirred overnight at room temperature. The salts are filtered off, the filtrate is concentrated by evaporation, the residue is taken up in methylene chloride and the solution is washed with water and then with 1N sodium hydroxide solution. The solvent is removed in vacuo and the residue obtained is 6.1 g of crude title compound which, recrystallised from tert.-butyl methyl ether, yields the title compound having a melting point of 71°-73° C.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:14]=O)[C:10]=1[C:11]([OH:13])=[O:12].[C:16]1([CH:22]2[N:26]=[CH:25][C:24](=[O:27])[O:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)[OH:29]>C(O)C>[C:11]([C:10]1[C:5]([O:4][CH3:3])=[CH:6][CH:7]=[CH:8][C:9]=1[CH:14]=[C:25]1[C:24](=[O:27])[O:23][C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:26]1)([OH:13])=[O:12].[O:23]1[CH:24]=[CH:25][NH:26][C:22]1=[O:29]
Reactant: O=C1C=NC(c2ccccc2)O1
Reactant: COc1cccc(C=O)c1C(=O)O
Reactant: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C=C2N=C(c3ccccc3)OC2=O)c1C(=O)O
Product: O=c1[nH]cco1
Reaction time: 0.58 h

Procedure:
To a stirred solution of 0.65 g. (11.5 mM) of potassium hydroxide in 23 ml. of ethanol is added 2.07 g. (11.5 mM) of 6-methoxyphthalaldehydic acid. To the resulting cooled (10°) milky suspension is added 1.89 g. (11.75 mM) of 2-phenyl-5-oxazolone. The mixture is warmed to 25° and stirred at this temperature for 35 minutes. A light orange precipitate forms. The mixture is made acidic with 3.45 ml. of 4N sulfuric acid and the resulting mixture kept at 0° for 1.5 hours and filtered. The collected solid is washed with a small amount of cold ethanol and then hexane. Air-drying gives the oxazolone 4-(2-carboxy-3-methoxybenzylidene)-2-phenyl-5(4H)-oxazolone as a yellow solid, m.p. > 320°.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>ClCCl>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]3[N:1]=[CH:2][CH:3]=[C:4]3[CH2:5]2)=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)nc1)N1Cc2ccnn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of 10 mmol of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]-benzodiazepine and 1.5 g of triethylamine in 20 ml of dichloromethane is added a solution of 2.11 g of 6-chloropyridine-3-carbonyl chloride in 5 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature diluted with 20 ml of dichloromethane and washed with 30 ml of 1N NaOH. The organic layer is washed twice with 20 ml of 1N NaOH, dried (Na2SO4) and the solvent removed. The residue is triturated with ether to give 3 g of solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:18])=[C:12]([S:14]([NH2:17])(=[S:16])=[O:15])[CH:13]=1)=[O:7].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>C(OCC)(=O)C.O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:18])=[C:12]([S:14]([NH2:17])(=[S:16])=[O:15])[CH:13]=2)=[O:7])[CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)CCCCCl)cc1S(N)(=O)=S
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1N1CCN(CCCCC(=O)c2ccc(C)c(S(N)(=O)=S)c2)CC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
A mixture of 5 g of 5-(5-chlorovaleryl)-2-methylthio-benzenesulfonamide, 3.4 g of 1-(2-methoxyphenyl)piperazine, 2.0 g of sodium carbonate and 25 ml of dimethyl sulfoxide was heated at 90° C. for 6 hours while stirring. After the reaction was finished, 100 ml of water and 100 ml of ethyl acetate were added to the reaction mixture and the stirring was continued for 30 minutes to produce crystals. The thus-produced crystals was filtered off to obtain 6.0 g of the titled compound (yield: 80.5%).