Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH:13]([CH3:15])[CH2:12][CH:11]([NH2:16])[CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].CCN(C(C)C)C(C)C.Cl.[F:40][C@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH:13]([CH3:15])[CH2:12][CH:11]([NH:16][C:18]([N:43]3[CH2:44][CH2:45][C@H:41]([F:40])[CH2:42]3)=[O:19])[CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1
Reactant: F[C@H]1CCNC1
Reactant: CC1CC(N)CC(Nc2nc(Cl)ncc2F)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1CC(NC(=O)N2CC[C@H](F)C2)CC(Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N1-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-1,3-diamine, 76b, (0.14 g. 0.54 mmol) in THF (2.5 ml) was added carbonyldiimidazole (0.10 g, 0.60 mmol) and iPr2NEt (0.28 mL, 1.62 mmol). The reaction was aged 2 hours at room temp, and treated with (S)-3-fluoropyrrolidine hydrochloride (0.07 g, 0.54 mmol). The reaction was stirred at room temperature for 2 days and then concentrated to dryness to afford 202 mg of (3S)—N-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5-methylcyclohexyl)-3-fluoropyrrolidine-1-carboxamide which was used without purification: LCMS RT=2.46 (M+1) 374.2, (M−1) 372.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[O:9]=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12].[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:12][C:11]([Cl:14])([Cl:13])[CH:10]1[CH:6]2[CH2:7][CH2:8][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5]2)[O:9]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: C1=CCCCCCC1
Agent: [Al+3]
Agent: [Cl-]
Product: ClC(Cl)(Cl)C1OC2CCCCC1CC2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
44.10 g (0.4 mole) of cyclooctene and 58.95 g (0.4 mole) of chloral in 60 ml of petroleum ether were initially taken in a 2-necked flask equipped with a magnetic stirrer, an internal thermometer and a drying tube. The mixture was cooled to ≤0° C. by means of a cold bath. 5.5 g (0.04 mole) of aluminum trichloride were added a little at a time in the course of 15 minutes, the temperature being kept at 0° C. Stirring was continued for a further 4 hours at this temperature, after which the mixture was left to stand for 15 hours at room temperature. For hydrolysis, the mixture was cooled to 0° C., and an equal volume of ice water was slowly added. The dark brown petroleum ether phase was separated off, filtered to remove the insoluble polymers and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated down in a rotary evaporator. The crude product was purified by fractional distillation under reduced pressure (105°-118° C.; 0.5 mm Hg). 78 g (0.3 mole; 75% by weight) of a mixture of two compounds in a ratio of 1:1 were obtained. The two compounds were separated by liquid chromatography over a silica gel column (diameter 5 cm, length 20 cm) using a 1:1 cyclohexane/methylene chloride mixture as the mobile phase. In addition to 3-(1'-hydroxy-2',2',2'-trichloroethyl)-1-cyclooctene, a compound of the probable structure 8-trichloromethyl-7-oxabicyclo[4.2.2]decane, of the formula ##STR37## was isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.CO/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].O.P(Cl)(Cl)(Cl)=O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: CO/C=C/C(=O)OC
Solvent: O
Solvent: CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 21 h
Yield: 78.7 %

Procedure:
0.62 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 0.57 g of methyl trans-3-methoxyacrylate, 46 mg of water and 6.4 mL of glacial acetic acid were mixed, then, 66 mg of phosphorus oxychloride was added dropwise into the mixture at an inner temperature of 25° C., the added mixture was stirred for 21 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 0.65 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 79%.
Reaction SMILES: [Br:1][C:2]([CH2:4]Br)=[CH2:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.Cl>C(OCC)C>[Br:1][C:2](=[CH2:3])[CH2:4][C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1
Reactant: C=C(Br)CBr
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: CCOCC
Product: C=C(Br)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A solution of 8 ml (0.0622 mol) of 2,3-dibromopropene in 50 ml diethyl ether was placed under a nitrogen atmosphere by use of a Firestone valve. While cooling in an ice water bath, a solution of 62 ml (0.062 mol) of 1M 4-chlorophenylmagnesium bromide in diethyl ether was added slowly via addition funnel. After stirring for 2 hours while warming to room temperature, the reaction was recooled in an ice bath and 50 ml of 1 N hydrochloric acid was then added via syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo. The residue was triturated with cold pentanes to yield 12.0 g of 1-(2-bromo-allyl)-4-chloro-benzene as an oil which was used in without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:12][CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH2:30]([C:32]1[N:36](C2N=C3C(N=C(OC4CCNCC4)N3C)=C(N3CCOCC3)N=2)[C:35]2[CH:60]=[CH:61][CH:62]=[CH:63][C:34]=2[N:33]=1)[CH3:31].FC(F)(F)C(O)=O>>[NH:15]1[CH2:16][CH:13]([O:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=[C:2]([N:33]2[C:34]4[CH:63]=[CH:62][CH:61]=[CH:60][C:35]=4[N:36]=[C:32]2[CH2:30][CH3:31])[N:10]=3)[CH2:14]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CCNCC3)n(C)c2n1
Reactant: Cn1c(OC2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CNC3)n(C)c2n1

Procedure:
The compound was prepared from tert-butyl 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yloxy)azetidine-1-carboxylate in a similar manner as that of 4-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-8-(piperidin-4-yloxy)-9H-purin-6-yl)morpholine, following General Procedures of Buchwald coupling shown in Scheme 3 and Boc-deprotection. The compound was used either as a mixture with unknown equivalent of trifluoroacetic acid or as a free base after treatment with aqueous base. Free base: 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.9 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 5.66-5.54 (m, 1H), 4.22 (s, 4H), 4.08-3.99 (m, 2H), 3.94-3.79 (m, 6H), 3.63 (s, 3H), 3.40-3.25 (m, 3H), 1.43 (t, J=7.5 Hz, 3H). LCMS: M+H+=435.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1.[H-].[Na+].Cl.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:20]([C:23]#[N:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:23]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH2:26][CH2:27][O:28][CH3:29])[N:16]=[CH:15][CH:14]=[C:13]2[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1)#[N:24]
Reactant: Oc1cccc(O)c1
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Oc3cccc(O)c3)c2cc1C#N
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
1,3-Dihydroxybenzene (110 mg, 1 mmol) was added to a stirred suspension of sodium hydride (60 mg, 2 mmol) in DMF (10 ml) and the mixture was stirred for 30 minutes. 4-Chloro-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (300 mg 1 mmol), (prepared as described for the starting material in Example 1), was added and the mixture was heated at 100° C. for 4 hours. The mixture was allowed to cool, was quenched with water and extracted with ethyl acetate (2×75 ml). The extracts were combined, washed with water (×2) and then brine and dried (MgSO4). The solvent was removed by evaporation and the residue was triturated with ethyl acetate/hexane, collected by filtration and dried to give 6-cyano-4-(3-hydroxyphenoxy)-7-(2-methoxyethoxy)quinoline (115 mg, 34%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>C1COCC1>[CH3:21][O:20][C:18]([C:13]1([CH2:26][CH2:25][CH2:24][CH2:23][Br:22])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: COC(=O)C1CCCC1
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(CCCCBr)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of diisopropylamine (150 mmol, 21 mL) in THF (100 mL) at −10° C. was added dropwise a 2.5M solution of n-butyl lithium in hexanes (145 mmol, 58 mL) while maintaining the temperature below 0° C. After the addition was complete, the solution was stirred for 30 min at 0° C., then it was cooled to −70° C. using a dry ice/acetone bath. A solution of methyl cyclopentanecarboxylate (100 mmol, 13.1 g) in THF (20 mL) was added dropwise at −70° C. maintaining the reaction temperature between −60 to −70° C. The mixture was then stirred for 1 h at −50 to −60° C. and a solution of 1,4-dibromobutane (100 mmol, 21.59 g) in THF (20 mL) was added dropwise and the light brown suspension was stirred for 1 h at −60 to −70° C. The cooling bath was removed and the reaction was allowed to equilibrate to room temperature and stirred overnight. The reaction mixture then was poured into a saturated solution of ammonium. chloride (200 mL) and the mixture was extracted with diethyl ether (2×100 mL). The combined extracts were washed with brine (150 mL), dried (MgSO4), filtered and the solution was concentrated under reduced pressure. The resulting residue was distilled at 120-133° C./2.5 mm Hg to obtain 12.8 g (48%) of 1-(4-bromobutyl)cyclopentanecarboxylic acid methyl ester as a colorless oil. HR MS: Obs. mass, 262.0565. Calcd. mass, 262.0568, (M+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=[O:7].S(Cl)([Cl:24])=O>>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:24])=[O:11])=[O:7]
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 2-(3-trifluoromethylbenzoyl)nicotinic acid (1.8 g) and thionyl chloride (10 ml) was heated at reflux for 3.5 hours. Excess reagent was removed by evaporation to yield 2-(3-trifluoromethylbenzoyl)nicotinoyl chloride as a red-brown gum (2 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][Si:9]([CH3:12])([CH3:11])Cl>C1COCC1.C[N-]C1C=CC=CC=1.C1([Mn+])C=CC=CC=1>[CH3:8][Si:9]([CH3:12])([CH3:11])[O:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: C[Si](C)(C)Cl
Agent: [Mn+]c1ccccc1
Agent: C[N-]c1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=CCCCC1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
- In another experiment, an enolate is prepared by the reaction of 100 mmol of phenylmanganese N-methyl-N-phenylamide: ##STR11## with 100 mmol of cyclohexanone in 200 ml of THF at 20° C. for 1 hour: ##STR12## 100 mmol of trimethylchlorosilane, ClSiMe3, are added to the resulting solution at 20° C. and the mixture is stirred for 30 minutes to produce the following reaction: ##STR13## 1-Trimethylsilyloxycyclohexene is obtained with a yield of 59%, compared with 77% for procedure A.
Reaction SMILES: S1C=CN=C1.Br[CH2:7][C:8](=O)[C:9]([OH:11])=[O:10].[NH2:13][C:14]([NH2:16])=[S:15]>>[NH2:16][C:14]1[S:15][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[N:13]=1
Reactant: NC(N)=S
Reactant: O=C(O)C(=O)CBr
Agent: c1cscn1
Product: Nc1nc(C(=O)O)cs1

Procedure:
Thiazole derivative IIb can be prepared according to any of a variety of methods. Ester of 2-amino-4- and 5-thiazolecarboxylic acids can be prepared by any method described in "Heterocyclic Compound", Elderfield, 5, 624. For example, reaction of bromopyruvic acid with thiourea gives 2-amino-4-thiazolecarboxylic acid (J. Am. Chem. Soc. 68, 266 (1946)) which is subjected to the Gattermann reaction to give 2-halogeno derivatives. Ester of 2-halogeno-5-methyl-4-thiazolecarboxylic acid can be obtained from 2-chloro-2,3-epoxybutyric acid ester with thiourea (Bull. Chem. Soc. Jap. 43, 2997 (1970)). Ethyl 2-halogeno-4-methyl-5-thiazolecarboxylate can be prepared from ethyl α-chloroacetoacetate with thiourea (J. Pharm. Soc. Jap., 76, 301 (1956)). These compounds are subjected to the Arndt-Eistert reaction with diazomethane or diazoethane or alkylation to give the corresponding acetic or propionic acid. Further, ethyl 2-chloro-4-methyl-5-thiazolecarboxylate can be prepared from ethyl 3-thiocyano-3-acetoxypropionate according to the method shown in U.S. Pat. No. 2,319,570. Ethyl 2-(2-bromo-4-thiazolyl)propionate is also prepared from ethyl 2-bromo-acetylpropionate with thiourea (J. Am. Chem. Soc. 63, 2946 (1941)). Thiazole derivative IIb substituted with an alkyl group other than methyl can be prepared by condensation following the method described above or alkylation of the thiazole derivatives prepared above.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][N:21]([C@@H:28]2[CH2:30][C@H:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C(=O)C(F)(F)F)[CH2:16][CH2:15]1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[K+:38]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C@@H:28]2[CH2:30][C@H:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:16][CH2:15]1)[C:6]([O-:8])=[O:7])#[N:2].[K+:38]
Reactant: COC(=O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)c(C#N)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cc(C(=O)[O-])ccc1CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a stirred solution of methyl 3-cyano-4-((4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoate (1.2 g, 2.402 mmol) in a mixture of methanol (15 mL) and water (2 mL) was added KOH (0.404 g, 7.21 mmol) at RT. Then the reaction mixture was stirred at 65° C. for 3 h. The reaction mixture was concentrated to afford (crude) potassium 3-cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (1 g, 107% yield). This was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[N:15]=[CH:16][C:11]3=[C:10]([N:22]3[CH2:29][CH:28]4[O:30][CH:24]([CH2:25][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]4)[CH2:23]3)[N:9]=2)=[CH:4][CH:3]=1.[Cl:38]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.NC1C=CN=CC=1.N(C1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C([N:80]3[CH2:87][CH:86]4O[CH:82](C[N:84]([C:89]([O:91]C(C)(C)C)=O)[CH2:85]4)[CH2:81]3)N=2)=CC=1)=C=O>ClCCl.O1CCCC1.C(N(CC)CC)C>[ClH:38].[N:80]1[CH:81]=[CH:82][C:85]([NH:84][C:89](=[O:91])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:13]=[C:12]4[N:14]([CH2:17][C:18]([F:20])([F:21])[F:19])[N:15]=[CH:16][C:11]4=[C:10]([N:22]4[CH2:29][CH:28]5[O:30][CH:24]([CH2:25][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]5)[CH2:23]4)[N:9]=3)=[CH:6][CH:7]=2)=[CH:86][CH:87]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc(N=C=O)cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc(N)cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Agent: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc(NC(=O)Nc5ccncc5)cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Product: Cl

Procedure:
A solution of tert-butyl 7-(6-(4-aminophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (0.48 g, 0.92 mmol) in dichloromethane (15 mL) was treated with triethylamine (1.2 mL), followed by a solution of triphosgene (0.14 g, 0.46 mmol). After the passage of 5 minutes, a solution of 4-aminopyridine (0.26 g, 2.8 mmol) in warm tetrahydrofuran was added to the tert-butyl 7-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 65% acetonitrile to provide tert-butyl 7-(6-(4-(3-pyridin-4-ylureido)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.hydrochloride as pale golden flakes. (282 mg, 45%). MS (ES+): 640.3 (M+H)+
Reaction SMILES: [C:1]([OH:16])(=[O:15])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:23]>O>[C:1]([O-:16])(=[O:15])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13].[Ag+2:23]
Reactant: [Ag+]
Reactant: O=C(O)/C=C/CCCCCCCCC(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])/C=C/CCCCCCCCC(=O)[O-]
Product: [Ag+2]

Procedure:
2.28 g of trans-traumatic acid (10 mmol) are suspended in 20 ml water at 4° C., neutralized using NaOH 1N, sheltered from light. The resulting suspension, kept at 4° C., is exposed to a nitrogen stream and a solution of 3.4 g AgNO3 in 20 ml water is slowly added drop by drop under continuous stirring.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]=[C:11]=[O:12])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1>>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:11]([NH:10][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[O:12])=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Product: COc1ccc(NC(=O)Nc2ccc3c(c2)OCO3)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 3,4-methylenedioxyphenyl isocyanate and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) using a similar procedure to Example 11.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[CH3:56][O:57][CH:58]1[CH2:61][NH:60][CH2:59]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([N:60]4[CH2:61][CH:58]([O:57][CH3:56])[CH2:59]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: COC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cncc(F)c4)nc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a DMF (0.3 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 30 mg, 0.092 mmol) and HATU (42 mg, 0.11 mmol) was added 3-methoxyazetidine 2,2,2-trifluoroacetate (22 mg, 0.11 mmol), followed by dropwise addition of DIEA (0.048 mL, 0.27 mmol). After stirring for 30 minutes at ambient temperature, the reaction was directly purified by reverse-phase chromatography (5 to 50% acetonitrile/water) to yield the final product as white solid (25 mg, 69%). LCMS (apci) m/z=397.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:16]O.P(Br)(Br)[Br:19]>ClCCl>[Br:19][CH2:16][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: CCN1CCN(c2ccc(CO)c(Cl)c2)CC1
Solvent: ClCCl
Product: CCN1CCN(c2ccc(CBr)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[2-chloro-4-(4-ethylpiperazin-1-yl)phenyl]methanol was dissolved in dichloromethane (30 mL) at 0° C. under nitrogen. Phosphorus tribromide (4.2 mL, 42 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of 10% NaHCO3 solution (5 mL). After 10 minutes, Na2SO4 (30 g) was added. The solvent was filtered and evaporated to provide 1-[4-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[C:19]([O-:22])(O)=O.[Na+].C(Cl)(Cl)=O.[N-]=C=O.[NH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([N:42]2[C:50]3[CH:49]=[CH:48][N:47]=[CH:46][C:45]=3[CH:44]=[CH:43]2)=[CH:34][CH:33]=1>ClCCl.C1COCC1>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:19]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([N:42]3[C:50]4[CH:49]=[CH:48][N:47]=[CH:46][C:45]=4[CH:44]=[CH:43]3)=[CH:34][CH:33]=2)=[O:22])[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Nc1ccc(-n2ccc3cnccc32)c2ccccc12
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [N-]=C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1c(NC(=O)Nc2ccc(-n3ccc4cnccc43)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C

Procedure:
N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (75 mg, 0.266 mmol, 1 equiv.) was dissolved in 20 mL dichloromethane and 20 mL of saturated aqueous NaHCO3 solution was added. The biphasic mixture was cooled to 0° C. and phosgene (˜2 M solution in toluene, 0.44 mL) was added to the organic layer via syringe in one portion without stirring. The mixture was then stirred vigorously for 10 min, then the layers were separated. The aqueous layer was extracted once with dichloromethane and the combined organics were dried (Na2SO4), filtered and most of the dichloromethane was removed in vacuo, leaving the toluene. To this isocyanate residue was then added 1-(4-aminonaphthalen-1-yl)pyrrolo[3,2-c]pyridine (Example 1) (46 mg, 0.177 mmol, 1 equiv.) dissolved in 5 mL anhydrous THF. The mixture was left to stir at room temperature overnight, then the solvents were removed in vacuo. The residue was purified by column chromatography on SiO2 using dichloromethane/MeOH eluent mixtures. The title compound (34 mg) was isolated as a pink foam.