Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54](CO)=[CH:53][CH:52]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][C:54]2[CH:57]=[CH:58][C:51]([C:50]([F:60])([F:59])[F:49])=[CH:52][CH:53]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccc(C(F)(F)F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 51 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (70 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (105 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-trifluoromethylbenzyl alcohol (63 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (60 mg, yield 48%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>CN(C)C=O>[OH:19][C:15]1[CH:14]=[C:13]([N:12]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1cccc(O)c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
452 g (3.0 mol) of phthalic anhydride are used as initial charge in 1.6 l of DMF (dimethylformamide) in a round-bottomed flask. 334 g (3.0 mol) of 3-aminophenol are added slowly to this mixture. The mixture is stirred at 140° C. for 8 hours. During this period, water is removed by distillation by way of the head of a column. The mixture is permitted to cool to room temperature, and the precipitated solid is removed by suction filtration. The solid is washed first with water and then with ethanol, and is then dried in vacuo. This gives 650 g of a beige-coloured solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[C:15](=[O:37])[C:16]([C:26]2[N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:29]=[CH:28][CH:27]=2)=[N:17][N:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:19]=1>CN(C=O)C>[CH3:12][O:13][C:14]1[C:15](=[O:37])[C:16]([C:26]2[N:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:29]=[CH:28][CH:27]=2)=[N:17][N:18]([C:20]2[CH:21]=[N+:22]([O-:9])[CH:23]=[CH:24][CH:25]=2)[CH:19]=1
Reactant: COc1cn(-c2cccnc2)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: COc1cn(-c2ccc[n+]([O-])c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF solution (2.0 ml) of m-chloroperbenzoic acid (0.398 mg) was added a DMF solution (12.0 ml) of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-(pyridin-3-yl)pyridazin-4(1H)-one at 0° C., and the mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration to give the title compound (168 mg).
Reaction SMILES: C([NH:4][C:5]([NH2:7])=[NH:6])(=O)C.N1CCCC1.CCO.[Br:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@@H:24]1[NH:29][C:28](=[O:30])/[C:27](=[C:31](/O)\[CH3:32])/[C:26](=O)[CH2:25]1>CCOC(C)=O>[NH2:7][C:5]1[N:4]=[C:31]([CH3:32])[C:27]2[C:28](=[O:30])[NH:29][C@@H:24]([C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[Br:16])[CH2:25][C:26]=2[N:6]=1
Reactant: CC(=O)NC(=N)N
Reactant: C/C(O)=C1/C(=O)C[C@H](c2ccc(F)cc2Br)NC1=O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCNC1
Product: Cc1nc(N)nc2c1C(=O)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 160 °C
Yield: 72.2 %

Procedure:
A microwave vial charged with acetylguanidine (800 mg, 7.9 mmol) was added pyrrolidine (3.25 mL, 39 mmol), 5 mL of EtOH and 31G (1.3 g, 3.9 mmol). The mixture was heated in a microwave at 160° C. for 10 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with 1M NaHSO4 (40 mL×2), brine, dried over Na2SO4, concentrated in vacuo. The resulting solid was purified by column chromatography (2-5% MeOH in DCM gradient) to give the product 31H as a light yellow crystalline solid (989 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 (s, 3H) 2.83 (dd, J=16.29, 5.94 Hz, 1H) 3.22 (dd, J=16.42, 6.06 Hz, 1H) 4.84-5.06 (m, 1H) 7.11 (br. s., 2H) 7.19-7.40 (m, 2H) 7.61 (dd, J=8.59, 2.53 Hz, 1H) 7.98 (d, J=3.28 Hz, 4H). ESI-MS: m/z 351.0 (MH+).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.N#N.C1(C)C=CC=CC=1.C([Li:35])CCC>CCCCCC>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Li:35])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]c1ccc(S(=O)(=O)c2ccccc2)cc1

Procedure:
A solution of 30 grams (0.1 mole) of 4-bromophenyl phenyl sulfone in 500 ml. of tetrahydrofuran was cooled to -100° C. in a liquid nitrogen-toluene slush, and 42 ml. (0.1 mole) of 2.38 M n-butyl lithium in hexane was added, forming 4-phenylsulfonyl-phenyl lithium. After about 10 minutes, 9.5 grams (0.05 mole) of diethyl dichlorophosphoramide was added, and the reaction mixture was allowed to warm slowly to room temperature, and then to stand a room temperature for 18 hours, forming diethyl bis [4-(phenylsulfonyl)phenyl] phosphoramide. Next, 125 ml. of 6 M HCl was added, and the reaction mixture was heated under reflux for 4 hours to hydrolyze the phosphoramide group. The tetrahydrofuran was removed by distillation, and 7.5 grams of almost white solid, M.P. 115°-130° C., was collected by filtration. This solid was recrystallized from tetrahydrofuran to give 7 grams (28% yield) of the bis[4-(phenylsulfonyl)phenyl] phosphinic acid product, m.p. 155°-165° C.
Reaction SMILES: C(Cl)(=O)C.C(OC([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([O:18][C:19]2[CH:38]=[CH:37][C:22]3[C:23]4[N:27]([CH2:28][CH2:29][O:30][C:21]=3[CH:20]=2)[CH:26]=[C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[N:24]=4)[CH2:13]1)=O)(C)(C)C>CO>[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([O:18][C:19]2[CH:38]=[CH:37][C:22]3[C:23]4[N:27]([CH2:28][CH2:29][O:30][C:21]=3[CH:20]=2)[CH:26]=[C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[N:24]=4)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3c(c2)OCCn2cc(-c4ccccn4)nc2-3)C1
Solvent: CO
Solvent: CC(=O)Cl
Product: c1ccc(-c2cn3c(n2)-c2ccc(OC4CCCNC4)cc2OCC3)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
To an ice-cooled solution of MeOH (4 mL) was added dropwise acetyl chloride (1.5 mL) and the mixture was stirred for 30 min at RT. A solution of impure 3-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy)piperidine-1-carboxylic acid tertbutyl ester coming from the previous step in MeOH (1 mL) was then added and the reaction mixture was stirred for 2 h at RT. A white solid was filtered off and the filtrate was concentrated in vacuo. The resulting residue was purified by HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 35-85% 0.1% NH4OH in acetonitrile/water, RT 10.6 min) affording 8-(Piperidin-3-yloxy)-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (13 mg, 6% over two steps).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]([S:22]([NH:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[C:27]=2[CH3:32])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C.[F:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45]>>[CH3:31][C:28]1[C:27]([CH3:32])=[C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][CH:13]=[CH:14][N:15]=3)=[CH:10][C:5]=2[CH2:4][N:3]([CH3:2])[C:44](=[O:45])[C:43]2[CH:47]=[CH:48][CH:49]=[C:41]([F:40])[CH:42]=2)(=[O:24])=[O:23])[O:30][N:29]=1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2cccc(F)c2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide, monohydrochloride (25 mg, 0.053 mmol, prepared as described in Step (A) of Example 28), triethylamine (13.3 mg, 0.13 mmol) was added and followed by 3-fluorobenzoyl chloride (8.3 mg, 0.053 mmol). The reaction was stirred at room temperature overnight and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 29% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 71% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (18 mg, 61%) as a white solid, m.p. 125°-135° C. (amorphous).
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1C(Cl)=O.CO.S(=O)(=O)(O)O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1[C:4]([CH2:6][C:7]([O:9][CH3:2])=[O:8])=[O:5]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC(=O)c1c(F)cccc1F

Procedure:
To 3.6 g (25 mmole, 1 eq) of Meldrum's acid and 6.1 g of 4-dimethylamino-pyridine in 60 ml of methylenechloride was added with stirring, 4.4 g (25 mmole) of 2,6-difluorobenzoylchloride. The temperature was maintained at 0° throughout the addition period and for three additional hours of stirring under argon atmosphere. Most of the methylene chloride was then removed by distillation at 25° or less using a water aspirator to maintain reduced pressure. There was then added 60 ml of anhydrous methanol containing 25 mmole of conc. sulfuric acid.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17].Cl>O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[NH:7][C:6]=2[CH:8]=1
Reactant: CC(C)(N)CO
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Agent: Cl
Solvent: O
Product: CC(C)(CO)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 14.1 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.3 g, 1.17 mmol) in 2-amino-2-methyl-1-propanol (2 ml, 21 mmol) was stirred for 40 h at 120° C. in a sealed flask. Water (5 ml) was added to the cooled solution and pH was adjusted to <2 by the addition of 4M hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water, and recrystallised from methanol/water to give 51 mg (14%) of the pure title compound; mp 224-226° C.; 1H-NMR (DMSO-d6): δ1.30 (s, 6H), 3.43 (s, 2H), 5,17 (br s, 1H), 6.63 (br s, 1H), 7.10 (s, 1H), 10.90 (s, 1H); MS: m/e 309/311 (M+).
Reaction SMILES: [Cl-].[P:2](N)([O-])[O:3][CH:4](C(C)C)C(C)C.[CH:13]([N:16]([CH:19]([CH3:21])[CH3:20])CC)([CH3:15])[CH3:14].[OH:22][CH2:23][CH2:24][C:25]#[N:26]>C1COCC1>[C:25]([CH2:24][CH2:23][O:22][CH2:4][O:3][PH:2][N:16]([CH:13]([CH3:14])[CH3:15])[CH:19]([CH3:20])[CH3:21])#[N:26]
Reactant: CC(C)C(OP(N)[O-])C(C)C
Reactant: N#CCCO
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)N(POCOCCC#N)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Diisopropylmethyl phosphoramidite chloride (10.7 g, 52.5 mmol) was added to a magnetically stirred solution of THF (100 ml), diisopropylethylamine (27.5 ml, 157.5 mmol) and 3-hydroxypropionitrile (7.2 ml, 105 mmol) at 0° C. After 4 hours, the mixture was warmed to room temperature and stirred for an additional 2 hours. The hydrochloride salt was removed from the reaction mixture by filtration through a scintered glass funnel. The resulting filtrate was recovered, diluted 1/1 with ethyl acetate, and washed with three 100 ml portions of 5% NaHCO3. The organic portion was then dried over Na2SO4 and evaporated to yield the crude product which was dissolved in a mixture of dichloromethane/hexane/triethylamine (6/4/1 v/v/v) (50 ml) and applied to a column of silica gel (175 g) which had been equilibrated with the same solvent mixture. The column was eluted with the solvent mixture and fractions (20 ml) were collected. Fractions which contained the desired product were identified as 2-cyanoethoxymethoxy-N,N-diisopropylaminophosphine (hereinafter referred to as Compound III) represented by the formula set forth below: ##STR6## wherein i-Pr is isopropyl. Fractions containing Compound III were pooled, evaporated, and then coevaporated with toluene (3×5 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][N:6](C2CCCCO2)[C:5](=[O:15])[CH:4]=1.Cl.[OH-].[Na+]>CO>[OH:15][C:5]1[N:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cnn(C2CCCCO2)c(=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnnc(O)c1
Temperature: 35 °C
Yield: 65.3 %

Procedure:
5-Methoxy-2-(tetrahydro-2H-pyran-2-yl) -3(2H)-pyridazinone (2035 g, 9.69 moles) and 2 L of methanol were added to a 22 L round bottomed flask equipped with a heating mantle, reflux condenser and mechanical stirrer. The mixture was warmed to 35° C. and 8 L of 6N HCl was added and then the mixture was heated to reflux for 2 h. The reaction mixture was then cooled slightly and transferred to a glycol cooled 22 L flask where the mixture was cooled further to 30° C. The mixture was made basic (pH 13-14) by cautious addition of 50% NaOH in small portions. The basic mixture was extracted with CH2Cl2 (4×3 L). The aqueous phase was then acidified with concentrated HCl (pH 1-2) to precipitate the product. The product was collected by vacuum filtration on a Buchner funnel. The product was dried to constant weight on a fluid bed dryer at 70° C. This afforded 798 g (65% yield) of 3-hydroxy-5-methoxypyridazine as a white solid which was recrystallized from methanol, mp=253°-255° C.
Reaction SMILES: N1(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)C=CC=N1.Cl.[F:32][C:33]([F:48])([F:47])[C:34]1[N:35]=[CH:36][C:37]([NH:40][C@H:41]2[CH2:45][CH2:44][CH2:43][C@@H:42]2[NH2:46])=[N:38][CH:39]=1.[CH3:49][O:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH3:61])[C:52]=1[C:53](O)=[O:54]>>[CH3:61][O:60][C:56]1[CH:57]=[CH:58][CH:59]=[C:51]([O:50][CH3:49])[C:52]=1[C:53]([NH:46][C@H:42]1[CH2:43][CH2:44][CH2:45][C@@H:41]1[NH:40][C:37]1[CH:36]=[N:35][C:34]([C:33]([F:32])([F:47])[F:48])=[CH:39][N:38]=1)=[O:54]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1cccn1
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for 2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 31) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 213 mg, 0.75 mmol) and 2,6-dimethoxybenzoic acid (CAS number 1466-76-8; 151 mg, 0.83 mmol) except this was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][CH:10]2[CH3:13])=[CH:5][C:4]=1[O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].[Cs].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[N:9]([CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=3)[CH:10]2[CH3:13])=[CH:5][C:4]=1[O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2C
Reactant: COc1cccc(CBr)c1
Agent: [Cs]
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(CN2C(C)c3cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 35.3 %

Procedure:
To a solution of 240 (170 mg, 0.45 mmol) in acetone (1.5 ml) was added cesium C(Ar)bonate (162 mg, 0.5 mmol) followed by 3-methoxy benzyl bromide (0.063 ml, 0.54 mmol). The reaction mixture was stirred at rt for 23 h. The resulting solution was diluted with water and extracted with ethyl acetate (3×). The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification (Flashmaster; 10 g, 100% hex to 95% hex:5% EtOAc over 25 min) afforded the title compound (79 mg, 35%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 0.94 (3H, s, CH3), 1.07 (18H, d, J=6.7 Hz, 6×SiCHCH3), 1.09 (3H, s, CH3), 1.15-1.29 (3H, m, 3×CH), 1.20 (3H, d, J=6.2 Hz, CH3CH), 2.37 (1H, d, J=15.3 Hz, one of CH2), 2.94 (1H, d, J=15.3 Hz, one of CH2), 3.50 (1H, d, J=17.3 Hz, one of CH2), 3.71 (1H, q, J=6.2 Hz, CHCH3), 3.76 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.09 (1H, d, J=17.3 Hz, one of CH2), 6.48 (1H, s, CH), 6.59 (1H, s, CH), 6.71 (1H, dd, J=7.7, 2.2 Hz, CH), 7.0 (1H, d, J=7.7 Hz, CH), 7.09 (1H, brs, CH), 7.19 (1H, t, J=7.9 Hz, CH). 13C NMR (100 MHz; CDCl3) 12.85 (CH3), 17.92 (CH3), 18.69 (CH3), 24.35 (CH3), 30.03 (CH3), 44.29 (CH2), 53.29 (CH2), 53.72 (C), 55.08 (OCH), 55.47 (OCH3), 57.40 (OCH3), 111.06 (CH), 111.84 (CH), 112.92 (CH), 118.13 (CH), 119.34 (CH), 126.70 (C), 128.81 (CH), 132.34 (C), 143.23 (C), 146.35 (C), 148.81 (C), 159.46 (C). LC/MS (ES+) tr=7.09 min, m/z 498.42 (M++H). HPLC tr=7.03 min (>98%).
Reaction SMILES: [Cl:1]C1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H:18]2[C@@H:22]([O:23][CH2:24]C)[CH2:21][N:20]([C:26]3SC=CN=3)[CH2:19]2)=NC=1CC.[Cl:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:59][CH3:60])[C:45]([NH:50][C@H:51]2[C@@H:55]([O:56][CH2:57][CH3:58])[CH2:54][NH:53][CH2:52]2)=[N:46][C:47]=1[CH2:48][CH3:49].ClC1C=C(OC)C=CN=1>>[ClH:1].[Cl:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:59][CH3:60])[C:45]([NH:50][C@H:51]2[C@@H:55]([O:56][CH2:57][CH3:58])[CH2:54][N:53]([C:19]3[CH:18]=[C:22]([O:23][CH3:24])[CH:21]=[CH:26][N:20]=3)[CH2:52]2)=[N:46][C:47]=1[CH2:48][CH3:49]
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Agent: COc1ccnc(Cl)c1
Product: CCO[C@H]1CN(c2cc(OC)ccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Product: Cl

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine and 2-chloro-4-methoxypyridine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ 8.6, 8.08, 7.22, 7.12, 7.05, 6.90, 6.40, 5.92, 5.40, 5.00, 4.32, 4.20–4.10, 3.95, 3.86, 3.52, 2.81, 2.60, 1.33, 1.26, 1.18; IR (diffuse reflectance) 2966, 2934, 2685 (b), 2036 (w), 1974 (w), 1657, 1607 (s), 1493, 1463, 1442, 1404, 1293, 1265, 1232, 826 cm−1 HRMS (ESI) calcd for C27H34N5O3Cl+H1 512.2429. found 512.2417.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H]1[C@H](C(O)=O)CC=CC1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CC=CC[C@H]1C(=O)O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 155.6 %

Procedure:
Preparation A1, Step 3: A sample of (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72 g) was dissolved in CH2Cl2 (750 mL) prior to the addition of CDI (50.9 g). After 2.5 h water was added, and the solution was extracted with CH2Cl2. The combined organic layers were dried, filtered, and concentrated. The resulting material was dissolved in CH2Cl2 and ammonia gas was bubbled through the solution for 1.5 h. After stirring overnight, the majority of the solvent was removed and Et2O was added. The product precipitated as a white solid and was collected to give (1R,6S)-6-carbamoyl-cyclohex-3-enyl)-carbamic acid benzyl ester (61.5 g). MS found: (M+H)+=275.3.
Reaction SMILES: CC1C=CC(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)N=1.Cl[C:17]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1.ClC1N=C(C)C=CC=1C(O)=O>>[N:12]1([C:17]2[C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:13]=[CH:14][N:15]=[N:11]1
Reactant: O=C(O)c1cnccc1Cl
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Agent: Cc1ccc(C(=O)O)c(Cl)n1
Product: O=C(O)c1cnccc1-n1ccnn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 70 substituting 4-chloronicotinic acid for 2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated for C11H10N4O3, 246.22; m/z found 247.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.09 (t, J=2.8 Hz, 1H), 7.92-7.86 (m, 3H), 7.66 (dd, J=8.7, 3.3 Hz, 1H), 2.17 (dd, J=2.5, 1.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH2:18][CH2:19]Cl.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]3[N:27]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:19][CH2:18][C:3]=3[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:5][C:6]=12)#[N:12]
Reactant: CCOC(=O)c1nc2c(C#N)cnn2c(Cl)c1CCCl
Reactant: NC1CCCCC1
Product: CCOC(=O)c1nc2c(C#N)cnn2c2c1CCN2C1CCCCC1
Yield: 96.5 %

Procedure:
The intended compound was obtained in 96.5% yield in the same manner as in Synthesis Example (5) using ethyl 7-chloro-6-(2-chloroethyl)-3-cyanopyrazolo[1,5-a]-pyrimidine-5-carboxylate and cyclohexylamine.
Reaction SMILES: I[C:2]1[C:3]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([OH:34])[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:3]([NH:8][C@H:9]([C:11]3[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15](=[O:23])[C:14]4=[CH:24][CH:25]=[CH:26][N:13]4[N:12]=3)[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=2)[CH:31]=[C:32]([OH:34])[CH:33]=1
Reactant: C[C@H](Nc1ncncc1I)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncncc1-c1cc(O)cc(F)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 33.9 %

Procedure:
(S)-2-(1-((5-Iodopyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (30 mg, 0.07 mol) was treated with (3-fluoro-5-hydroxyphenyl)boronic acid (15 mg, 0.10 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (87 mg, 0.1 mmol) and sodium carbonate (2M, 147 μl, 0.29 mol) according to the method described in Example 3 to give 15 mg (52% yield) of the title compound as a white solid. Purity 99%.