Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[C:5]1([C:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]#[C:20][C:21]3[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH2:15][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:5]1([C:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]#[C:20][C:21]3[N:26]=[CH:25][C:24]([NH:27][CH2:1][CH2:2][CH3:3])=[CH:23][CH:22]=3)[CH2:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCC=O
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCCNc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of propionaldehyde (0.18 mL, 2.5 mmol), 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) (0.83 g , 2.7 mmon) and glacial acetic acid (0.14 mL, 2.5 mmol) in 20 mL of dichloroethane is treated with sodium triacetoxyborohydride (0.79 g, 3.7 mmol) under nitrogen and is stirred at room temperature for 18 hours. The reaction is quenched with saturated aqueous sodium bicarbonate, diluted with dichloromethane, and the organic layer is dried (sodium sulfate) and concentrated under reduced pressure. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound, containing 0.20 mol of water; mp 138°-139° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH2:13][OH:14].O.[OH-].[Na+].S(OC)(O[CH3:22])(=O)=O>C1(C)C=CC=CC=1>[CH3:22][O:14][CH2:13][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([CH2:9][OH:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: COS(=O)(=O)OC
Reactant: OCc1c(F)c(F)c(CO)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COCc1c(F)c(F)c(CO)c(F)c1F
Temperature: 65 °C
Yield: 100.8 %

Procedure:
Into a reaction vessel that was charged nitrogen, 5.00 g (23.1 mmol) of 2,3,5,6-tetrafluoro-1,4-benzenedimethanol, 15.00 g of water and 6.85 g (46.3 mmol) of 27% aqueous sodium hydroxide solution were charged subsequently, and heated to 65° C. with stirring. The starting compound was completely dissolved to be clear solution. Then, the reaction mixture was allowed to cool to room temperature with stirring. At this time, some precipitate was observed. To the reaction mixture, 20.0 g of toluene was added and then 4.33 g (32.6 mmol) of dimethyl sulfate was added dropwise over 7.5 hours at room temperature. After the addition, the pH of the aqueous layer became 13.5. The layers of the reaction mixture were separated, and the pH of the aqueous layer was adjusted to about 3 by adding 10% sulfric acid. The aqueous layer was extracted with 30 ml of ethyl acetate, and the combined organic layers were washed- with 30 ml of water, concentrated, and dried under a reduced pressure to give 5.22 g of crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol. The crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol was subjected to content analysis by GC internal standard method (Analytical method 1 given later). GC area percentage of the crude product: 85% of the objective compound, 1% of the starting compound and 13% of the by-product compound Content analysis by GC internal standard method: 85% of the objective compound and 86% of the yield of pure compound
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1COCC1.CCO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: Fc1ccc(Nc2ccnc(Cl)n2)cc1
Temperature: 65 °C
Reaction time: 10 h
Yield: 30.5 %

Procedure:
To a solution of 2,4-dichloropyrimidine (260 g, 1.75 mol) in THF (780 mL) and EtOH (3100 mL) is added NaHCO3 (244 g, 2.91 mol). To the slurry which results is added 4-fluoroaniline (162 g, 1.46 mol) in one portion and the resulting mixture allowed to warm to 65° C. and held at this temperature for 10 hours. The reaction if not completed in a single day can be cooled over night. Re-heating the next day to 70° C. for an additional 10 hours is usually sufficient for completion of the reaction. The reaction solution is diluted with EtOAc (4.5 L) and washed with water (3×2 L). The combined aqueous layers are extracted with EtOAc (3 L). The combined organic layers are dried over MgSO4 and filtered. The filter cake is washed with acetone (2×1 L) then with 5% MeOH/acetone (2×500 mL). The filtrate is concentrated until a thick slurry is obtained (ca. 1 L volume), hexane (3.5 L) is added and the solution cooled to about 4° C. for 16 hours. The thick slurry is collected by filtration, washed with hexane (2×500 mL), and dried (20 mmHg, room temperature) to afford 99.43 g (79.3% yield) of the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.06 (d, J=6.0 Hz, 1H), 7.59 (m, 2H), 7.11 (m, 2H), 6.64 (d, J=6.0 Hz, 1H); MS (ESI) m/z 224 (M+1).
Reaction SMILES: C(NCC)C.[Li]CCCC.[C:11]1([PH2:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)(O[CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH:35](OP(C2C=CC=CC=2)(C2C=CC=CC=2)=O)[CH3:36])[CH3:28])=O)C=CC=CC=1.[OH-].[Na+]>C1COCC1.CC(OC)(C)C.O>[CH3:36][CH:35]1[C:30]2[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]([CH3:28])[P:17]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(OP(=O)(c1ccccc1)c1ccccc1)c1ccccc1C(C)OP(=O)(c1ccccc1)c1ccccc1
Reactant: Pc1ccccc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: CC1c2ccccc2C(C)P1c1ccccc1

Procedure:
Under an atmosphere of nitrogen a Schlenk flask was charged with diethylamine (0.584 g, 8 mmol), to which a solution of n-BuLi (2.5 ml 1.6 N-solution in hexanes, 4 mmol) was added drop wise under efficient stirring. To the slightly hazy solution was then added phenyl phosphine (0.110 g, 1 mmol) which led to the formation of a yellow solution. This mixture was diluted with THF (2 ml), and immediately afterwards was added under efficient stirring a solution of diphenyl-phosphinic acid 1-{2-[1-(diphenyl-phosphinoyloxy)-ethyl]-phenyl}-ethyl ester (0.567 g, 1 mmol) in THF (made up to 2 ml total volume) drop wise over two minutes into the Schlenk flask. When the addition was complete, the mixture was stirred for another ten minutes. To the mixture was then added water (3 ml), sodium hydroxide (1 ml 40% solution in water), and TBME (15 ml). The mixture was stirred for 10 minutes, by which time two clear layers had formed. The aqueous layer was removed via syringe, and the organic layer was dried (Na2SO4). Removal of the solvent in vacuum left the product as colourless oil. 1H/13C-NMR (CDCl3, 300 MHz, HSQC/HMBC, indices A/B relate to syn/anti to P-lone pair) δ/δ 1.21 (dd, J=7.3 Hz, J=11.2 Hz)/14.45 (s) (B-CH3); 1.62 (dd, J=7.7 Hz, J=18.6 Hz)/21.73 (d, J=29.9 Hz) (A-CH3); 3.59 (dq, J=16.6 Hz)/40.04 (d, J=8.5 Hz) (A CHMe); 3.77 (dq, J=2.3 Hz)/35.57 (d, J=13.5 Hz) (B CHMe); 7.17 (m)/125.27 (d, J=1.1 Hz) (A Ar ortho-CH); 7.26 (m)/126.88, 7.26/127.22 (2 Ar meta-CH); 7.36 (m)/125.60 (d, J=1.3 Hz) (B Ar ortho-CH); 7.21 (m)/128.15 (d, J=7.2 Hz) (Ph meta-CH); 7.27 (m)/129.26 (d, J=1.0 Hz) (Ph para-Ch); 7.27 (m)/133.81 (d, J=19.8 Hz) (Ph ortho-CH); 135.90 (d, J=22.1 Hz) (Ph ipso-C); 145.09 (d, J=3.8 Hz) (B Ar ipso-C); 149.04 (d, J=2.3 Hz) (A Ar ipso-C). 31P-NMR δ 22.14.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:32][C:31]([F:34])([F:33])[CH2:30][CH2:29][CH2:28][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=4)[N:8]=3)[CH2:13][CH2:14]2)=[CH:19][CH:20]=1
Reactant: FC(F)(F)CCCBr
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)CCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 200 °C
Yield: 36.5 %

Procedure:
4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (obtained as described in Example 5.2, preparation of starting materials) (200 mg, 0.55 mmol), 4-bromo-1,1,1-trifluorobutane (526 mg, 2.75 mmol) and potassium carbonate (152 mg, 1.10 mmol) were suspended in DMA (4 mL) and sealed into a microwave tube. The reaction was heated to 200° C. for 30 minutes in the microwave reactor and cooled to room temperature. The mixture was evaporated to dryness and redissolved in DCM (20 mL) and the solution was washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-{4-[4-(4,4,4-trifluorobutoxy)phenyl]piperidin-1-yl}-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (95 mg, 37%) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl.O.C(#N)C>[CH3:8][C:6]1[CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[CH:4][N:5]=1
Reactant: Cc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2ccccc2)ncn1
Yield: 46 %

Procedure:
First, in a recovery flask equipped with a reflux pipe were put 4.90 g of 4-chloro-6-methylpyrimidine, 4.80 g of phenylboronic acid, 4.03 g of sodium carbonate, 0.16 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, in the flask were further put 2.28 g of phenylboronic acid, 2.02 g of sodium carbonate, 0.082 g of Pd(PPh3)2Cl2, 5 mL of water, and 10 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and extraction with dichloromethane was carried out. The obtained solution of the extract was washed with a saturated sodium carbonate aqueous solution, water, and saturated saline in this order, and dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as a developing solvent in a volume ratio of 9:1, so that a pyrimidine derivative Hmppm, which was the objective substance, was obtained (orange oily substance, yield of 46%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). The synthesis scheme of Step 1 is shown in (b-1) below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:34])[N:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.C(O)(=O)C.[NH2:43][CH2:44][C:45]1([C:48]#[N:49])[CH2:47][CH2:46]1.[Na]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:27]3[CH2:32][CH2:31][CH:30]([NH:49][CH2:48][C:45]4([C:44]#[N:43])[CH2:47][CH2:46]4)[CH2:29][CH2:28]3)=[O:34])[N:9]=2)[CH:7]=1
Reactant: O=C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: N#CC1(CN)CC1
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#CC1(CNC2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 4.3 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-oxo-1-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (201.7 mg 0.38 mmol) in dichloromethane (1.0 mL) was added acetic acid (0.3 mL, 5.24 mmol). To this was then added 1-(aminomethyl)cyclopropanecarbonitrile (47.2 mg, 0.466 mmol). This was then stirred at room temperature for 5 minutes. The reaction was then cooled to 0° C. and to this was added sodium triacetyoxyborohydride (124.1 mg, 0.56 mmol) and stirred for 3 hours and let warm to room temperature in the process. LC/MS (method 31) shows product as a major peak. The reaction was quenched by adding 2 mL water followed by 10 mL saturated sodium bicarbonate solution. This was the extracted with dichloromethane and the organic layers were dried with solid anhydrous magnesium sulfate powder, filtered and concentrated to give a white solid. 20.6 mg was then purified by reverse phase HPLC purification to afford 10.2 mg of N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(4-(((1-cyanocyclopropyl)methyl)amino)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LC/MS (method 38) [M+H]+=624.2, RT=2.80 min. 1H NMR (400 MHz, DMSO-d6) 9.75 (s, 1H), 9.34 (dd, J=7.0, 1.7 Hz, 1H), 8.68 (dd, J=4.3, 1.6 Hz, 1H), 8.67 (s, 1H), 8.30 (s, 1H), 7.63 (dd, J=8.8, 2.7 Hz, 1H), 7.56 (d, J=2.7 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.29 (dd, J=7.0, 4.2 Hz, 1H), 7.25 (t, J=73.0 Hz, 1H), 5.23 (d, J=4.7 Hz, 2H), 4.12 (d, J=12.7 Hz, 1H), 3.84 (d, J=13.7 Hz, 1H), 3.14 (t, J=11.9 Hz, 1H), 2.85 (t, J=11.9 Hz, 1H), 2.71-2.65 (m, 3H), 2.02 (s, 1H), 1.83 (t, J=16.2 Hz, 2H), 1.33-1.12 (m, 4H), 0.94 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(C)(C)N
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)(C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-aminoisobutyrate (prepared from 2-aminoisobutyric acid (Aldrich) using General Procedure H), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.25 in CHCl3/MeOH 95:5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.[Cl:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.Cl>C1C=CC=CC=1.CC(C)=O>[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3ccccc23)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)c(C)c2)c2cccc3ccccc23)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-naphth-1-yl-methane (0.3 gm, 0.008 mol), anhydrous K2CO3 (2.0 gm), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.3 gm, 0.0017 mol) and anhydrous acetone (25 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off, and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate washed with water, dried over Na2SO4 and concentrated to give an oil. This oil was passed through basic alumina using benzene as eluent. Solvent was distilled off. The oil thus obtained was treated with ethanolic HCl. The solvent was evaporated and compound was crystallized with absolute alcohol and anhydrous ether to give the title compound as a salt of general formula I. Yield 170 mg(46%).
Reaction SMILES: [CH2:1]([C:9]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:21]2[CH:20]=[C:19]([C:22]#[C:23][Si](C)(C)C)[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:22]([C:19]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:21]=2[CH:20]=1)#[CH:23]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1ccc2c(c1)C(CCCCCCCC)(CCCCCCCC)c1ccccc1-2
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.9 %

Procedure:
To a solution of (9,9-dioctyl-9H-fluoren-2-ylethynyl)-trimethylsilane (10.3 g, 21.2 mmol) in ethanol was added potassium carbonate (2.92 g, 21.2 mmol). The mixture was stirred at room temperature for 20 hours and then filtered. The filtrate was evaporated to dryness and the residue taken up in hexane. Washing with water, drying over magnesium sulfate and evaporation gave an oil characterized as 2-ethynyl-9,9-dioctyl-9H-fluorene (7.20 g, 82% yield).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([C:18]3[N:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]4=[C:20]([C:27]4[CH:28]=[C:29]([CH:38]=[CH:39][CH:40]=4)[C:30]([NH:32]/[C:33](=[N:36]/[H])/[CH2:34]O)=[O:31])[N:19]=3)=[O:17])[CH:8]=2)[NH:3]1>CN(C=O)C.CCOCC>[CH3:34][C:33]1[N:32]=[C:30]([C:29]2[CH:28]=[C:27]([C:20]3[N:19]=[C:18]([C:16]([C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2](=[O:1])[N:11]([CH2:12][CH2:13][CH3:14])[C:10]5=[O:15])=[O:17])[N:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=34)[CH:40]=[CH:39][CH:38]=2)[O:31][N:36]=1
Reactant: [H]/N=C(\CO)NC(=O)c1cccc(-c2nc(C(=O)c3ccc4[nH]c(=O)n(CCC)c(=O)c4c3)n3ccccc23)c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(-c5nc(C)no5)c4)c4ccccn34)cc2c1=O
Yield: 86.2 %

Procedure:
A solution of 0.1 g (0.19 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}-N-[(1E)-hydroxyethanimidoyl]benzamide in 3 ml of DMF is heated at 120° C. for 5 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in dyethyl ether, filtered, and then dried under reduced pressure at 40° C. overnight. 0.083 g of a yellow solid is obtained.
Reaction SMILES: [S:1]([CH2:5][C:6]([OH:8])=[O:7])([OH:4])(=[O:3])=[O:2].[CH2:9](O)[CH3:10]>>[S:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: O=C(O)CS(=O)(=O)O
Reactant: CCO
Product: CCOC(=O)CS(=O)(=O)O
Temperature: 80 °C

Procedure:
2.21 g (15.8 mmol) of sulfoacetic acid was suspended in 30 ml of ethanol, and the suspension was heated at 80° C. under reflux for 5 hours. The solvent was distilled off to obtain the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:14]=[C:13]2[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:12]=32)[CH:6]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Br:19][C:17]1[CH:16]=[CH:15][C:12]2[C:13]3[N:7]([CH2:8][CH2:9][O:10][C:11]=2[CH:18]=1)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[N:14]=3
Reactant: COC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 45 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid methyl ester (1.000 g, 0.003095 mol) in tetrahydrofuran (7.50 mL) and water (4.5 mL) was added lithium hydroxide (0.2964 g, 0.01238 mol). The reaction was stirred at 45° C. for 2 h. The mixture was acidified to pH=1 with 2N HCl. The resulting precipitate was filtered and rinsed with cold water to obtain 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (860 mg) as an off-white solid. MS (ESI+) 309.0/311.0
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:26]=[CH2:27])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: C=Cc1c(NC(C)=O)cc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Temperature: 110 °C
Yield: 60 %

Procedure:
4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid methyl ester (0.5 g, 1.29 mmol), tributyl(vinyl)tin (0.821 g, 2.58 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.091 g, 0.129 mmol), and tetrabutylammonium triphenyldifluorosilicate (1.4 g, 2.58 mmol) were combined in acetonitrile (3 ml) and heated to 110° C. for 15 min in a CEM microwave reactor. The cooled reaction mixture was concentrated onto silica gel and purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (0.293 g, 60% yield) as a white solid, mp 143-145° C. 1H NMR (CDCl3) δ 7.66 (m, 1H), 7.22 (d, 1H), 7.12 (m, 1H), 6.85 (dd, 1H), 5.66 (dd, 1H), 5.57 (dd, 1H), 4.61 (br s, 2H), 3.97 (s, 3H), 3.94 (d, 3H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]([NH2:12])=[S:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:3])=[O:20])[C:10]([NH2:12])=[S:11]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(N)=S
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCC(O)CCCN(CCCCCCC(=O)OC)C(N)=S
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-[1-(4-hydroxynonyl)thioureido]heptanoic acid (10.3 g., 0.03 mole) (Example 3) in ether (50 ml.). The resulting solution is allowed to stand at room temperature for 4 hours. Then acetic acid is added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution, brine, then dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-[1-(4-hydroxynonyl)thioureido]heptanoate as a viscous oil.