Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ncccc1I
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccnc2Cl)CC1
Temperature: 100 °C
Yield: 95 %

Procedure:
Dissolve 2-chloro-3-iodopyridine (2.0 g, 8.37 mmol) in toluene (7 mL). Add piperazine-1-carboxylic acid t-butyl ester (1.2 g, 6.4 mmol), followed by the addition of tris(dibenzylideneacetone)dipalladium(0) (0.12 g, 0.13 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (0.23 g, 0.39 mmol), and sodium t-butoxide (0.93 g, 9.7 mmol). Heat at 100° C. for 3.5 hr. Concentrate and partition the residue between EtOAc and water. Extract the aqueous phase twice with ethyl acetate. Wash combined organic layers with brine. Dry the organic extracts (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes), to give 4-(2-Chloro-pyridin-3-yl)-piperazine-1-carboxylic acid t-butyl ester (95%). MS (ES): m/z=298 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]([NH2:15])[CH3:14]>C(Cl)Cl>[CH2:13]([NH:15][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH3:14]
Reactant: CCN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CCNS(=O)(=O)c1ccc(OC)cc1
Yield: 112 %

Procedure:
4-Methoxybenzene-1-sulfonyl chloride (619.5 mg, 2.999 mmol) was dissolved in DCM (10 mL) and ethylamine (4.6 mL, 2.0 M in THF, 9.2 mmol) was added, and the reaction flask was put in a water bath and stirred under nitrogen. After stirring at RT over the weekend, the suspension was filtered, and the solid was washed with DCM. The filtrate was concentrated and dried under high vacuum to provide N-ethyl-4-methoxybenzenesulfonamide (723 mg, 89% yield). MS (ESI pos. ion) m/z: 216 (MH+). Calculated exact mass for C9H13NO3S: 215.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[Na+].[Cl-]>O1CCCC1>[C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][O:19][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1nc2ccccn2c1C#Cc1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C(OCc1nc2ccccn2c1C#Cc1ccccc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
0.117 g (0.467 mmol) of (3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl) methanol were solubilised in 4 ml of tetrahydrofurane with magnetic stirring. 0.228 g (0.7 mmol) of cesium carbonate and 0.61 ml (0.513 mmol) of morpholine-4-carbonyl chloride were added. The mixture was stirred at r.t. for 16 h. 1.22 ml (1.026 mmol) of additional morpholine-4-carbonyl chloride were added and the mixture was stirred at r.t. for 2 d before being treated with 10 ml of a saturated NaCl aqueous solution. The aqueous phase was extracted with 3×10 ml of ethyl acetate. The combined organic phases were dried on Na2SO4 which was then removed by filtration. The crude residue was purified by preparative HPLC and 0.078 g (yield=46%) of (3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)methylmorpholine-4-carboxylate were obtained as a beige solid. LC-MS: m/z=362 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.60 (d, J=6.7 Hz, 1H), 7.66 (dd, J=11.0, 5.4 Hz, 3H), 7.47 (dd, J=4.1, 1.3 Hz, 4H), 7.14 (t, J=6.4 Hz, 1H), 5.33 (s, 2H), 3.48 (s, 4H), 3.34 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:19]([F:21])[F:20])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](Cl)=O.CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:19]([F:21])[F:20])[N:6]2[CH2:13][C:14]1[N:17]=[C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[O:16][N:15]=1
Reactant: [H]/N=C(/Cn1c(C(F)F)cc2c(Cl)c(C#N)ccc21)NO
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3ccccn3)n2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of (1Z)-2-[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.011 g, 0.035 mmol) in anhydrous THF (1.5 mL), under N2, was added picolinoyl chloride hydrochloride (0.0066 g, 0.037 mmol) and Et3N (0.0078 g, 0.077 mmol). The mixture was stirred at rt for 30 min. The reaction was monitored by TLC and additional acid chloride (0.003 g, 0.018 mmol) and Et3N (0.0035 g, 0.035 mmol) were added and stirring continued at rt for 1 h. The mixture was then heated in a microwave at 120° C. for 20 min, and subsequently at 150° C. for 2 h. Upon cooling, the mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with 0.1N HCl, sat'd NaHCO3 solution and sat'd brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (5-50% EtOAc-hexanes gradient), followed by a second purification by radial chromatography (5-70% EtOAc-hexanes gradient). The product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.005 g, 38% yield): MS (ES) m/z 386 (M+1).
Reaction SMILES: O[N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10].S(Cl)(Cl)=O>C(Cl)Cl>[C:3]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: COC(=O)c1cc(C=NO)ccc1OC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(C#N)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 5-((hydroxyimino)methyl)-2-methoxybenzoate (1.04 g, 4.94 mmol) was dissolved in methylene chloride (25 mL) and cooled to 0° C. The reaction was treated with thionyl chloride (0.59 mL, 8.1 mmol) and stirred at 0° C. for 2 h. After warming to room temperature, the reaction was diluted with methylene chloride, washed with saturated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated to afford 0.87 g (92%) which was used without further purification. 1H-NMR (CDCl3, 500 MHz) δ 8.09 (d, J=2.1 Hz, 1H), 7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H). Mass spec.: 192.02 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:29][CH2:28]2)=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:31][CH2:32]2)=[CH:19]1
Reactant: NCCCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCC(c2c[nH]c3ccccc23)CC1

Procedure:
Batch size: 6.3 g (42.5 mmol) 3-(3-pyridyl)-acrylic acid, 11 ml (127 mmol) oxalyl chloride and 10.5 g (38.7 mmol) 4-[4-(1H-indol-3-yl)-piperidin-1-yl]-butylamine.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:13])=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
In a 100 ml round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.00 g, 2.69 mmol) was dissolved in DMF (6 ml). tert-Butylamine (1.7 ml, 16.2 mmol) was added followed by HATU (1.12 g, 2.95 mmol). The yellow suspension was stirred at room temperature for 72 h then quenched with water and extracted with a mixture of diethyl ether and EtOAc. The organic layers were washed twice with water and once with brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether to afford 989 mg (86%) of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as an off-white powder. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.40 (s, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 5.65 (s, 2H), 3.46-3.58 (m, 2H), 1.54 (s, 9H), 0.84-0.98 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.B1(O)[O:29][CH2:28][C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2>C1COCC1.C(Cl)Cl.CCCCCC>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:27]=4[CH2:28][OH:29])[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: OB1OCc2ccccc21
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1NC(=O)c2c1c(-c1ccccc1CO)cc1[nH]c3ccc(O)cc3c21
Yield: 57 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-(hydroxymethyl)benzeneboronic acid cyclic monoester according to the procedure described in example 8 gave 9-Hydroxy-4-[2-(hydroxymethyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (503) (I; Ar=2-(hydroxymethyl)phenyl) in a 57% yield, mp (THF/CH2Cl2/hexane) 270–280° C. (dec). 1H NMR [(CD3)2SO] δ 11.76 (br s, 1H), 10.96 (br s, 1H), 9.25 (br s, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.43 (td, J=7.6, 1.2 Hz, 1H), 7.31 (td, J=7.4, 0.9 Hz, 1H), 7.23 (dd, J=7.5, 1.0 Hz, 1H), 7.06 (dd, J=8.7, 2.5 Hz, 1H), 5.00 (t, J=5.4 Hz, 1H), 4.33 (dd, J=13.6, 5.2 Hz, 1H), 4.24 (dd, J=13.5, 5.3 Hz, 1H). Found: C, 68.41; H, 4.29; N, 7.59. C21H14N2O4,1/2H2O requires C, 68.66; H, 4.12; N, 7.63.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)=[CH:8][C:9]=1[NH:10]C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(F)cn2)cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(-c2ccc(F)cn2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-tert-butoxycarbonylamino-5-(5-fluoropyridin-2-yl)-thiophene-2-carboxylic acid methyl ester (80 mg) in dichloromethane (1.35 mL) was mixed with trifluoroacetic acid (0.15 mL) and stirred at room temperature overnight. The solvent was then removed in vacuo, and the residue was taken up again in dichloromethane and washed twice with saturated NaHCO3 solution and once with water. The dichloromethane phase was dried over sodium sulfate and concentrated. The product with the molecular weight of 252.27 (C11H9FN2O2S) was obtained in this way; MS (ESI): 253 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)=[O:4].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>O>[O:20]1[CH2:19][CH:18]1[CH2:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][N:5]([CH:3]=[O:4])[CH2:14][CH2:13]2
Reactant: O=CN1CCc2cc(O)ccc2C1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=CN1CCc2cc(OCC3CO3)ccc2C1
Yield: 82.8 %

Procedure:
A solution of 6.8 g of sodium hydroxide in 90 ml of water is added dropwise over 1 hour to a mixture of 26.6 g of 2-formyl-1,2,3,4-tetrahydro-6-hydroxy-isoquinoline and 42.5 g of epichlorohydrin at 60° C. The reaction mixture is held at this temperature for an additional hour, then allowed to cool and extracted several times with methylene chloride. The organic phase, dried over sodium sulfate, is evaporated and the residue is rubbed with diethyl ether. 29.0 g of 6-(2,3-epoxy-propoxy)-2-formyl-1,2,3,4-tetrahydro isoquinoline are obtained. m.p. = 78° - 79° C. (ethyl acetate - diethyl ether).
Reaction SMILES: C(O)[N:2]1[C:6](=[O:7])[N:5](CO)[CH:4]2[N:10](CO)[C:11]([N:13](CO)[CH:3]12)=[O:12].[Cl-].[NH4+]>O>[CH:4]12[NH:10][C:11](=[O:12])[NH:13][CH:3]1[NH:2][C:6]([NH:5]2)=[O:7]
Reactant: O=C1N(CO)C2C(N1CO)N(CO)C(=O)N2CO
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: O=C1NC2NC(=O)NC2N1
Temperature: 148.88888888888889 °C
Reaction time: 0.05 h

Procedure:
The following experimental procedure was utilized to test physical properties of nonwoven substrates impregnated with the tetramethylol glycoluril-containing VAE copolymer emulsions. The copolymer binder was applied to the substrate using the Atlas padding technique. The emulsions were initially diluted with deionized water to 9.0% solids and the pH was adjusted to 4.0 with ammonium chloride. Whatman #4 chromatography paper was saturated with the binder, the samples were dried, heated at 300° F. for five minutes and then subjected to tensile testing. The strips were immersed in solvent for three minutes and then placed in an Instron (2" jaw span, 1"/min. crosshead speed) for testing.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:12]([NH2:14])=[O:13].[CH:15]1([CH2:21][C:22](OC)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:21][C:22]2[NH:14][C:12](=[O:13])[C:3]3[CH:4]=[N:5][N:6]([CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[C:2]=3[N:1]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCC(CC)n1ncc(C(N)=O)c1N
Reactant: COC(=O)CC1CCCCC1
Product: CCC(CC)n1ncc2c(=O)[nH]c(CC3CCCCC3)nc21

Procedure:
The product is obtained in analogy to Example 1/stage 1c) starting from 200 mg (1.02 mmol) of 5-amino-1-(1-ethylpropyl)-1H-pyrazole-4-carboxamide and 482 mg (3.06 mmol) of methyl cyclohexylacetate.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:32]2([CH3:33])[C:9](=[CH:10][CH:11](Br)[C@@H:12]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:27])[CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:36][C:37](=[O:39])[CH3:38])[CH2:6]1)(=[O:3])[CH3:2].CC1C=C(C)N=C(C)C=1.C1(C)C(C)=CC=CC=1>C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@:32]2([CH3:33])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:27])[CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:36][C:37](=[O:39])[CH3:38])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(F)(F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCC(F)(F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 140 °C

Procedure:
A mixture of 1.33 g (0.0019 mol) of [1α,3β,7ξ]-7-bromo-24,24-difluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.8 mL of s-collidine and 10 mL of xylene was heated at reflux (140° C.) for 0.5 hr and cooled. The mixture was diluted with 30 mL of benzene. This solution was washed with 10% aqueous sulfuric acid, and saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on 0.06-0.20 mm silica gel to yield [1α,3β]-24,24-difluorocholesta-5,7-dien-1,3,25-triol 1,3-diacetate, [α]D25 -31° (c 0.4, CHCl3), mp 130°-132°. UV max (C2H5OH) 261 (ε 7750), 270 (ε 11,200), 281 (ε 12,100) and 293 (ε 7100).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O>[C:12]([CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=1)([OH:14])=[O:13]
Reactant: COC(=O)COc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 91.4 %

Procedure:
4-Methoxycarbonylmethoxy-benzoic acid methyl ester 1 (50 grams, 223 mmol) was added to a solution of 2.5 M sodium hydroxide (250 mL) and heated to 80° C. for 5 hours. The reaction mixture was dilated with water (100 mL) and pH adjusted to 1 with concentrated HCl. Crude 76 was filtered, dried and given hot ethyl acetate slurry to give 76 (40 grams, 91.4%) as a white powder. M.p: >280° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>CC(O)C>[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COCCN
Solvent: CC(C)O
Product: COCCNc1ccc(C(=O)O)cn1
Yield: 19.3 %

Procedure:
A microwave vial is charged with 6-chloronicotinic acid (1 g, 6.35 mmol), 2-methoxyethylamine (1.214 mL, 13.96 mmol) and IPA (3.5 mL) sealed and irradiated in a microwave synthesizer at 180° for 40 min. The reaction was cooled, concentrated and purified by SiO2 chromatography eluting with a MeOH/DCM gradient (5% to 10% MeOH containing 0.5% HOAc) to afford 0.24 g of 6-(2-methoxy-ethylamino)-nicotinic acid (330) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[F:19])[N:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:27][CH2:18][C:13]1[C:12]([F:19])=[C:11]([O:10][C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([Cl:1])[N:3]=2)[C:16]([Cl:17])=[CH:15][CH:14]=1
Reactant: Cc1ccc(Cl)c(Oc2cc(C#N)cc(Cl)n2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CBr)c2F)c1
Yield: 57.2 %

Procedure:
2-chloro-6-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-4-pyridinecarbonitrile (3.65 g, 12.28 mmol) and NBS (2.187 g, 12.28 mmol) were combined in carbon tetrachloride (100 mL) with a catalytic amount of AIBN (0.101 g, 0.614 mmol) and stirred at reflux for 16 h. The reaction mixture was washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by chromatography on 120 g silica gel eluted with 0% to 10% Et2O in hexanes to give the desired product, 2-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (2.64 g, 7.02 mmol, 57.2% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm (8.01 (s, 1H), 7.96 (s, 1H), 7.50-7.62 (m, 2H), 4.75 (s, 2H). LC-MS (ES+) m/z 374.98, 377.01, 379.03 [M+H].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[O:7]=[S:8]1(=[O:32])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]([C:25](=[N:27][OH:28])[NH2:26])[CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:29][CH2:30][CH2:31][C:10]2=[N:9]1.N1C=CC=CC=1>CN(C=O)C>[O:32]=[S:8]1(=[O:7])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]([C:25](=[N:27][O:28][C:2]([O:4][CH2:5][CH3:6])=[O:3])[NH2:26])[CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:29][CH2:30][CH2:31][C:10]2=[N:9]1
Reactant: CCOC(=O)Cl
Reactant: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)ON=C(N)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reaction time: 0.5 h

Procedure:
65 μl (0.65 mmol) of ethyl chloroformate are added dropwise to a solution, cooled to 0° C., of the product obtained in Step A (244 mg, 0.65 mmol) in 1.5 ml of DMF and 59 μl (0.72 mmol) of pyridine. Stirring is carried out at 0° C. for 30 minutes and precipitation of the reaction mixture is brought about using water. The precipitate is filtered off to yield the title product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].Cl.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[C:30](=[O:35])[CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CN1CCNCC1=O
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 8.5 h

Procedure:
6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B, 3.0 g, 8.58 mmol), KF (2.52 g, 42.9 mmol), 1-methylpiperazine-2-one hydrochloride (3.88 g, 25.7 mmol), N-ethyldiisopropylamine (5.99 mL, 35 mmol) were suspended in NMP (60 mL). The RM was stirred at 180° C. for 8.5 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and then crystallized in EtOAc to afford the title compound as a white solid (tR 3.19 min (conditions 1), (tR 8.84 min (conditions 2), MH+=423.2, 1H-NMR in DMSO-d6: 8.94 (d, 1H); 8.45 (d, 1H); 7.84 (d, 1H); 7.63 (s, 1H); 7.59 (m, 2H); 7.08 (d, 1H); 4.98 (m, 1H); 4.02 (d, 1H); 3.73 (d, 1H); 3.60 (m, 2H); 3.31 (m, 1H); 3.25 (m, 1H); 2.80 (s, 3H); 1.88 (d, 3H)).
Reaction SMILES: N#N.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[O:17][C:18](=[O:39])[C:19]4[C:24]([C:25]=3[C:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:15])[N:11]=[C:12](I)[C:5]=12.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[C:45]([OH:47])[CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C1COCC1.O.C(O)=O.O.CC#N>[CH:18]([OH:39])=[O:17].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[O:17][C:18](=[O:39])[C:19]4[C:24]([C:25]=3[C:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:15])[N:11]=[C:12]([C:43]3[CH:44]=[C:45]([OH:47])[CH:46]=[C:41]([F:40])[CH:42]=3)[C:5]=12
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)OC(C)(C)C)CC1)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: Cl
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(c1oc(=O)c2ccccc2c1C1=CCNCC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 85 °C
Reaction time: 3 h
Yield: 303.8 %

Procedure:
N2 was bubbled for 5 min through a suspension of tert-butyl 4-(3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-5,6-dihydropyridine-1(2 H)-carboxylate (Intermediate D14, 735 mg, 1.197 mmol), 3-fluoro-5-hydroxyphenylboronic acid (0.28 g, 1.795 mmol), S-Phos-Pd-G2 (0.130 g, 0.179 mmol) and potassium phosphate (572 mg, 2.695 mmol) in THF/water 3:1 (8 ml). The mixture was heated at 85° C. for 1 hr by MW irradiation. A second run was performed in the same conditions on a mixture of reagents in the exact same amounts. The two reaction mixtures were combined and cone HCl (20 ml) was slowly added while stirring. Stirring went on at rt for 3 h, then volatiles were removed under reduced pressure. Purification by RP flash chromatography (Biotage Isolera, 60 g C18 column, gradient elution from 100:0 to 70:30 A/B in 15 CV; A: water/MeCN 95/5+0.01% HCOOH, B: water/MeCN 5/95+0.01% HCOOH) yielded 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formate (0.990 g, 1.818 mmol, 76% yield) as a pale yellow powder.