Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].[H-].[Na+].Cl>CN(C)C=O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[O:20])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C1CC(=O)C2CCC1C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O

Procedure:
A solution of bicyclo[3,2,1]octane-2,4-dione (0.552 g, 4.0 mmole), 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.77 g, 8.0 mmole), and 60% sodium hydride in mineral oil (0.176 g, 4.4 mmole) in dimethylformamide (150 mL) was stirred at 0° C. for 1 hour and heated at 45–50° C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (30% dichloromethane/hexane) to give a clear oil as the expected product. The oily product was crystallized with ethyl acetate/hexane in a dry ice bath to afford the title compound as a white solid, mp=136–137° C.; MS (−) ESI m/z=358 (M−H)−. Analysis for C16H13ClF3NO3 Calculated: C: 53.42; H, 3.64; N, 3.89. Found: C: 53.37; H, 3.57; N, 3.67.
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10]>O>[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6]
Reactant: O=C(O)C(=O)O
Agent: [V+5]
Agent: [O-2]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 1300 °C

Procedure:
Granulated alumina (8-16 mesh) is heated at 1300° C for 4 hours. Water soluble salts of the promoters and vanadium pentoxide are suspended in 5 parts of water, heated to 80° C, and oxalic acid is added slowly to obtain a blue-colored vanadium oxalate solution. Sodium carbonate, as needed, is added and the alumina is also placed in the solution. The mixture is dried over a water bath with agitation. While air is pumped in, it is indurated in a furnace at 400° C for 16 hours to obtain the catalyst which is ready for use after cooling.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH:33]=[CH:32]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:42]2[CH2:43][CH2:44][N:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([Cl:28])[CH:30]=4)[N:35]=3)[CH2:40][CH2:41]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cc(Cl)ccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>CN(C)C=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH3:7]
Reactant: C1CNCCNC1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCNCC1
Reaction time: 4 h
Yield: 13.7 %

Procedure:
Ethyl bromoacetate (3.7 g, 18.4 mmol, Aldrich) was added in portions to a solution of homopiperazine (2.76 g, 27.6 mmol, Avocado) in N,N-dimethylformamide (15 mL) at room temperature over 1.5 h. The mixture was then stirred for additional 4 h followed by an aqueous workup. The crude was purified by column flash chromatography to give homopiperazine-acetic acid ethyl ester (471 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[NH2:27].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42]>CN(C=O)C>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([NH:27][C:26]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=1)=[O:42]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)CCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)CCCCCBr)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.4 %

Procedure:
WSC (2.11 g, 11 mmols) and HOBt (1.68 g, 11 mmols) were added to a DMF (15 ml) solution of 3,4,5-trimethoxyaniline (2.75 g, 15 mmols) and 6-bromohexanoic acid (1.95 g, 10 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.42 g (yield: 40%) of 6-bromo-N-(3,4,5-trimethoxyphenyl)hexanamide as colorless needle-like crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCN1CCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (230 mg, 1.06 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (234 mg, 1.37 mmol) and potassium carbonate (440 mg, 3.18 mmol) in 5 mL DMF was stirred at room temperature for 4 days. After this time, the mixture was poured into 20 mL H2O then extracted with 2×30 mL CH2Cl2. The organic layers were combined together, washed with brine (20 mL) and concentrated. Product was subjected to flash chromatography on the biotage using 5% 2M NH3 in MeOH/CH2Cl2 to give a yellow solid. Yield: 218 mg of yellow solid (71%). 1H NMR (CDCl3) δ: 8.14 (dd, J=2.7, 9 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 4.13 (t, J=7.5 Hz, 2H), 3.00 (t, J=6.9 Hz, 2H), 2.73-2.68 (m, 4H), 2.63-2.60 (m, 4H), 1.82-1.78 (m, 4H). MS (ESI): 290.2 (M+1, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(C#N)(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Nc1cccc(Cl)c1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1cccc(Nc2ncnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,4-dichloro-1,3,5-triazine (4.0 g, 26.7 mmol) and solid K2CO3 (16.0 g, 116 mmol) was suspended in AcCN (50 mL) under nitrogen at 0° C. followed by addition of 3-chloroaniline (3.4 g, 26.7 mmol). The mixture was stirred at 0° C. for 0.5 h. The reaction was quenched by pouring onto ice/water. The white solid which formed was collected by suction filtration, dried under vacuum then purified by column chromatography (elution with CH2Cl2) to give (3-chlorophenyl)-(4-chloro-[1,3,5]triazin-2-yl)amine MS m/z=241. Calc'd for C9H6Cl2N4: 240.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11]>ClCCl.[O-2].[Mn+2]>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: COc1ccc(CO)c(N)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C=O)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of (2-amino-4-methoxyphenyl)methanol (20 g, 131.0 mmol) and manganese oxide (68 g, 786.0 mmol) in dichloromethane (300 mL) was stirred at room temperature overnight. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=6:1) to give the title compound (7 g, 35%) as a yellow solid. MS (ES+) C8H9NO2 requires: 151, found: 152 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[N+](C1C=C(S(O[CH2:26][C@@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:26][C@@H:27]2[CH2:29][O:28]2)[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (456.3 mg, 1.76 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (300 mg, 1.76 mmol) and Cs2CO3 (687.4 mg, 2.11 mmol) in DMF (4.5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O, organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was opurified by silica gel flash chromatography (0-30% ethyl acetate in petroleum spirit) to give the subtitled compound (385 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccc(F)cc1
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Yield: 59.3 %

Procedure:
The title compound (cis/trans=98/2) was prepared as pale brown crystals in 59.3% yield in a similar procedure to that described in. Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=94/6) and 4-fluorobenzyl alcohol.
Reaction SMILES: [OH2:1].O.O.O.O.O.O.O.O.O.O.O.[P:13]([O-:17])([O-:16])([OH:15])=[O:14].[Na+].[Na+].O.O.O.O.O.O.O.P([O-])([O-])(O)=[O:28].[Na+].[Na+]>>[OH2:14].[OH2:28].[OH2:1].[OH2:14].[OH2:14].[OH2:14].[OH2:14].[OH2:14].[OH2:14].[OH2:14].[OH2:14].[OH2:14].[P:13]([OH:17])([OH:16])([OH:15])=[O:14]
Reactant: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Product: O=P(O)(O)O

Procedure:
Disodium hydrogenphosphate dodecahydrate is, however, incongruently melted to generate disodium hydrogenphosphate heptahydrate, which is precipitated at the bottom of the solution. When this solution is cooled, crystal of disodium hydrogenphosphate heptahydrate is grown owing to secondary nucleation (which means herein generation of new nuclear crystal in a supersaturated solution including seed crystal). This makes it impossible to obtain objective disodiun hydrogenphosphate dodecahydrate. In order to avoid the secondary nucleation, it is necessary to heat the solution until disodium hydrogenphosphate heptahydrate is dissolved. However, the solution is required to be cooled down to a temperature of approximately 22° C. to generate disodium hydrogenphosphate dodechydrate crystal in the solution. In this manner, there arises a problem of large supercooling (approximately 13° C.). In order to achieve comfortableness in the heating system for a building or the like, the heat storage material having such large supercooling is lack of practicability. Thus, it is required to suppress the supercooling to be approximately 5° C. or less.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27].C(N(CC)CC)C>O1CCCC1>[Cl:22][CH2:23][CH2:24][NH:25][C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1)=[O:27]
Reactant: O=C=NCCCl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCCl)ccc21
Reaction time: 8 h

Procedure:
4.2 g (0.015 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are heated at reflux for 3 hours in 80 ml of absolute tetrahydrofuran with 3.5 ml of chloroethylisocyanate and a catalytic amount of triethylamine. The mixture is left to stand at room temperature overnight. The solution is concentrated on a steam-bath and the residue is crystallised from ethyl acetate. There is obtained 1-(2-chloroethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea which melts at 240° C. with decomposition.
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:12]([NH:13][CH:14]=[CH:15][CH:16]=2)=[CH:11][N:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[C:17]2[C:12]([NH:13][CH:14]=[CH:15][CH:16]=2)=[CH:11][N:10]=1
Reactant: c1ccc(COc2ncc3[nH]cccc2-3)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ncc2[nH]cccc1-2
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A mixture of 5-benzyloxypyrrolo[3,4-b]pyridine (Compound 7f, 1.38 g, 6.15 mmol), 5% Pd/C (0.30 g), and absolute ethanol (25 mL) was shaken under a hydrogen atmosphere (3 atm) for 30 minutes. The resulting mixture was filtered through diatomaceous earth (Celite (trademark)), and the filtrate was evaporated under reduced pressure. The residual solid was triturated in ethyl ether to yield Compound 7i (0.80 g, 5.96 mmol, 97%) as an off-white crystalline solid: mp, 280.0°-282.0° C.: IR (KBr) 1,640, 1,615, 1,605, 1,455, 1,430, 1,400, 1,380, 1,365 cm-1 ; 1H NMR (DMSO-d6) δ 11.4 (br m, 2H), 7.56 (d, J=9.7 Hz, 1H), 7.16 (d, J=3.1 Hz, 1H), 6.01-5.93 (m, 2H); 13C NMR (DMSO-d6) 162.0, 131.9, 127.9, 125.0, 118.2, 112.2, 94.5; LRMS (m/z, relative intensity) 135 (41), 134 (M+, 100), 106 (66), 105 (42), 79 (59), 53 (31), 52 (52). Anal. calcd. for C7H6N2O: C, 62.68; H, 4.51; N, 20.88; found: C, 62.40; H, 4.40; N, 20.76.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:54]=[CH:53][C:27]([CH2:28][P:29](=[O:52])([O:33][C@@H:34]([CH2:36][CH2:37][N:38]4[CH:42]=[C:41]([B:43]5[O:47][C:46]([CH3:49])([CH3:48])[C:45]([CH3:51])([CH3:50])[O:44]5)[CH:40]=[N:39]4)[CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:55][CH3:56])[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=CC=3OC)N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CC[C@@H](O)C)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:54]=[CH:53][C:27]([CH2:28][P:29](=[O:52])([O:33][C@H:34]([CH2:36][CH2:37][N:38]4[CH:42]=[C:41]([B:43]5[O:47][C:46]([CH3:49])([CH3:48])[C:45]([CH3:50])([CH3:51])[O:44]5)[CH:40]=[N:39]4)[CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:55][CH3:56])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)O[C@H](C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Agent: C[C@H](O)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)O[C@@H](C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
Racemic Compound 70A was prepared analogously to Compound 69A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 1 g, 2 mmol) and (25)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-2-ol (Compound 70B, 400 mg, 2 mmol) to afford 454 mg of the title compound as a mixture of diastereomers (30%). MS (ESI): m/z=867.82/869.81 [M+H]+. UPLC: tR=1.69 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.O[NH:21][C:22]([C:24]1[S:25][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:27][CH:28]=1)=[NH:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]4[O:19][N:23]=[C:22]([C:24]5[S:25][C:26]([S:29]([NH2:30])(=[O:32])=[O:31])=[CH:27][CH:28]=5)[N:21]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(Cl)cc3)cn12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnc4ccc(-c5ccc(Cl)cc5)cn34)n2)s1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.36) (136 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (heptane/diethyl ether) as an off-white solid (160 mg, 70%). MS (ISP) 458.2 [(M+H)+]; mp 263° C.
Reaction SMILES: CC1(CO[C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15](COCC[Si](C)(C)C)[C:14]=3[N:13]=[CH:12][CH:11]=2)CCCNC1.Br.[OH-:34].[Na+].Cl>O1CCOCC1>[CH3:17][C:18]1([O:34][C:12]2[CH:11]=[CH:10][C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[NH:15][C:14]=3[N:13]=2)[CH2:10][CH2:11][CH2:12][NH:13][CH2:14]1
Reactant: CC1(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CCCNC1
Reactant: [OH-]
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(Oc2ccc3c(n2)[nH]c2cnc(C#N)cc23)CCCNC1
Temperature: 75 °C
Yield: 31 %

Procedure:
4-((3-methylpiperidin-3-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (52 mg, 0.12 mmol) was dissolved in 1,4-dioxane (0.5 mL) and then treated with 48% HBr(aq) (0.5 mL) and heated at 75° C. for 10 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as an off-white solid (11 mg, 31%). 1H NMR (400 MHz, d6-DMSO) δ 12.18 (s, 1H), 8.70 (d, J=0.9, 1 H), 8.51 (d, J=0.9, 1 H), 8.27 (d, J=9.0, 1H), 6.90 (d, J=9.1, 1H), 4.48 (s, 1H), 3.93-3.84 (m, 1H), 3.64 (d, J=13.0, 1H), 3.55-3.40 (m, 2H), 1.79 (m, 1H), 1.67-1.57 (m, 2H), 1.52 (m, 1H), 1.13 (s, 3H). LCMS (Method E): RT=3.73 min, M+H+=308.2.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH2:23][CH2:24][CH3:25]>C(C1C=CC=CC=1)(=O)C.CCOCC>[CH2:22]([O:8][C:7]1[C:4]([O:5][CH3:6])=[CH:3][C:2]([C:1]([OH:14])=[O:13])=[CH:12][C:9]=1[O:10][CH3:11])[CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)c1ccccc1
Product: CCCCOc1c(OC)cc(C(=O)O)cc1OC
Temperature: 135 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
Methyl syringate (10 g, 0.047 mol) and potassium carbonate (8.5 g, 0.061 mol) were stirred in acetophenone (100 mL) at 135° C. Butyl bromide (6.6 mL, 0.061 mol) was added dropwise over 1.5 h and the reaction was stirred over 18 h at 135° C. The reaction was cooled, filtered and the inorganic solids washed with acetone (20 mL). The combined filtrate was concentrated under high vacuum to give a red oil which was redissolved in ether (50 mL) and washed with 2N aqueous NaOH (2×10 mL) and water (3×10 mL). The organic layer was dried using anhydrous NaSO4 and the solvent removed under reduced pressure. The crude product was redissolved in methanol (250 mL) followed by addition of aqueous potassium hydroxide (44%, 20 mL). After heating at reflux for 2 h the reaction mixture was allowed to cool down to room temperature and left to rest over 18 h. The solvent was then concentrated under reduced pressure, the residue reconstituted in water (100 mL) and the resulting aqueous solution washed with ether (3×30 mL). The aqueous layer was acidified to pH=1 with 5N HCl and the precipitated product collected by filtration. The crude product was recrystallised from methanol to give 6.1 g, 51% yield of 4-butyloxy-3,5-dimethoxybenzoic acid as a colourless solid. 1H NMR (CDCl3) δ: 0.98 (t, J=5.1 Hz, 3H), 1.49 (m, 2H), 1.74 (m, 2H), 3.91 (s, 6H), 4.06 (t, J=5 Hz, 2H), 7.37 (s, 2H). MS m/z 255.4 (MH+).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCCCC1.C(NC(C)C)(C)C.Br[C:28]1[CH:41]=[CH:40][C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1.[C:42]1([C:48]#[CH:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1.C1C=CC=CC=1.[Cu]I>[C:34]1([C:32]([C:31]2[CH:40]=[CH:41][C:28]([C:49]#[C:48][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:29][CH:30]=2)=[O:33])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C(c1ccccc1)c1ccc(C#Cc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
In argon atmosphere, 0.15 M Solution of tri-tert-butylphosphine in cyclohexane (12.0 mL, 18.0 mmol) was added to a stirred suspension of copper(I) iodide (350 mg, 1.8 mmol) and dichloro(bisbenzonitrile)palladium (350 mg, 0.9 mmol) in tetrahydrofuran (100 mL) at ambient temperature. The mixture was stirred for 5 min, N,N-diisopropylamine (4.5 mL, 30 mmol) was added, the mixture was stirred for next 5 min and then a solution of 4-bromobenzophenone (3.92 g, 15 mmol) and phenylacetylene (2.30 g, 22.5 mmol) in tetrahydrofuran (20 mL) was added dropwise during 15 min. The reaction mixture was stirred at ambient temperature overnight and then diluted with benzene (200 mL). The benzene solution was washed with water (2×80 mL) and 1.5 M aqueous solution of tartaric acid (30 mL); the organic solution was dried with anhydrous magnesium sulfate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexane/ethyl acetate 95:5) yielding phenyl-[4-(phenylethynyl)phenyl]methanone.