Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@:11]23[CH2:16][C@@H:15]2[CH2:14][C:13](=O)[CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].C(OCC)(=O)C.CO.C(N(CC)CC)C>CO>[C:1]1([C@@:11]23[CH2:16][C@@H:15]2[CH2:14][CH:13]([NH2:24])[CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of (1R,5R)-1-(1-naphthyl)bicyclo[3.1.0]hexan-3-one (480 mg, 2.1 mmol) in methanol (60 mL) was added ammonium acetate (16.8 g, 210 mmol), stirred for 15 min at room temperature and sodium cyanoborohydride (1.08 g, 17 mmol) and the mixture was heated to 60° C. for 2 hours. The reaction was monitored by TLC (ethyl acetate/methanol/triethylamine(89:10:1)). The reaction mixture was concentrated under reduced pressure to remove methanol at 30° C., the crude mass was quenched with water (25 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL). The aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 1.5 g of crude oil, which was purified by preparative HPLC to give 280 mg (58%) of 99% pure product. 1H NMR δ(300 MHz,CD3OD): 1.10-1.23 (2H,m), 1.86-1.98 (2H,m) 2.25-2.31 (1H,m), 2.44-2.51 (1H,m), 2.90 (1H,m), 4.06-4.08 (1H,m), 7.33-7.56 (4H,m), 7.71-7.74 (1H,d,6 Hz), 7.82-7.85 (1H, d, 9 Hz), 8.20-8.28 (1H, m). 13CNMR(CD3OD): 140.75, 140.30, 135.49, 135.44, 133.92, 129.78, 128.61, 127.75, 127.09, 127.00, 126.72, 126.67, 126.58, 126.52, 125.68, 54.95, 43.05, 40.40, 36.35, 34.52, 33.88, 33.64, 25.86, 24.94, 23.70, 15.70.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][C:21]([OH:23])=[O:22].C(N(CC)CC)C>O>[CH2:1]([O:8][C:9]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 50 ml of water was suspended 2.5 g of N-(benzyloxycarbonyloxy)succinimide, and the suspension was stirred for 1 hour at room temperature. To this suspension was added 20 ml of an aqueous solution of 0.75 g of glycine and 1.4 ml of triethylamine, and the reaction mixture was stirred for 12 hours as it was, but the desired product, benzyloxycarbonylglycine, could not be obtained.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]3[C:17]([C:29]#[N:30])=[C:18]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:22])[S:19][C:13]=3[CH2:12]2)=[O:10])[CH2:4][O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(C#N)(C)=O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:29]#[N:30])=[C:18]([NH:20][C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[S:19][C:13]=2[CH2:12]1)=[O:10]
Reactant: CC1(C)OCC(COC(=O)N2CCc3c(sc(NC(=O)c4ccccc4)c3C#N)C2)O1
Agent: CC(=O)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: N#Cc1c(NC(=O)c2ccccc2)sc2c1CCN(C(=O)OCC(O)CO)C2
Yield: 80 %

Procedure:
0.26 mmol of 3-Cyano-2-[(1-phenyl-methanoyl)-amino]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester are dissolved in 10 ml AcCN/H20 (2/1) and 0.1 eq PTSA is added. After stirring over night, some triethylamine is added and the solvent removed. Recrystalization from ethanol gives the desired product in 80% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[CH:44]=[N:43][C:42](OS(C(F)(F)F)(=O)=O)=[CH:41]2.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:42]4[N:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[CH:39][CH:38]=[CH:37][C:36]=5[CH3:35])[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc2cc(OS(=O)(=O)C(F)(F)F)ncc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2cc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)ncc12
Temperature: 105 °C

Procedure:
To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (18.9 mg, 0.0403 mmol), trifluoromethanesulfonic acid 8-methylisoquinolin-3-yl ester (12.0 mg, 0.0412 mmol), and PS-PPh3-Pd (0.10 mmol/g loading; 26 mg, 0.0026 mmol; Argonaut) in 1,4-dioxane (0.70 mL, 9.0 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (26.7 mg, 0.0819 mmol) in H2O (0.20 mL, 11 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 minutes. The resin was filtered off and washed with DCM. The combined filtrate and washings were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC [20×20 cm plate, 500 μm layer of silica gel, eluting with 3% MeOH in DCM (2×) and 4% MeOH in DCM (2×)]. Material from the main band was collected and dried in vacuo overnight giving the title compound as a yellow glassy solid. 1H NMR (400 MHz, CDCl3): δ=9.50 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.02 (d, J=0.4 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.67 (d, J=0.4 Hz, 1H), 7.62 (dd, J=7.2, 8.4 Hz, 1H), 7.42 (dt, J=7.2, 0.8 Hz, 1H), 6.56 (brs, 2H), 4.38-4.19 (m, 3H), 2.92 (brs, J=11.0 Hz, 2H), 2.83 (s, 3H), 2.19 (brdd, J=2.2, 11.4 Hz, 2H), 1.95 (dq, J=4.0, 12.0 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=485.23 (100) [MH+], 429.16 (7) [MH+-isobutene]. HPLC: tR=2.88 min (polar—5 min, ZQ3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([C:10]([CH3:14])([CH3:13])[CH2:11]Cl)[CH:3]=1.Cl.N1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:14][C:10]([CH3:11])([CH3:13])[C:4]=2[CH:3]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CCl
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: CC1(C)COc2ccc(Br)cc21
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of 4-bromo-2-(2-chloro-1,1-dimethyl-ethyl)-1-methoxy-benzene (65 g, 0.234 mol), pyridine hydrochloride (121.8 g, 1.054 mol) and quinoline (110.67 mL, 0.936 mol) was refluxed at 164° C.–167° C. under argon for 5 hrs. After cooling to room temperature the reaction mixture was treated with ice-cold 6N HCl and extracted twice with ether. The organic layers were combined, dried (MgSO4), filtered and evaporated. The residue was purified on silica gel (10% ethyl acetate in hexane) to give 52 g of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (98%). 1H NMR (300 MHz; CDCl3): δ 1.32 (s, 6H), 4.23 (s, 2H), 6.67 (d, J=8.1 Hz, 1H), 7.19 (m, 2H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:18])[C:15]([CH3:17])=[CH2:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5].[ClH:19].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)C>[CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:18])[C:15]([Cl:19])([CH3:17])[CH3:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5]
Reactant: C=C(C)C(C)Oc1cc(OCC#CCC)ncn1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC#CCOc1cc(OC(C)C(C)(C)Cl)ncn1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution containing 0.3 g of 4-(2-pentynyloxy)-6-(1,2-dimethyl-2-propenyloxy)pyrimidine in 3 ml of tetrahydrofuran was added dropwise 3.66 ml of a 1 mol/l solution of hydrogen chloride in diethyl ether, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into a saturated aqueous sodium hydrogencarbonate solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium chloride, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of 4-(2-pentynyloxy)-6-(2-chloro-1,2-dimethylpropyloxy)pyrimidine (the present compound (41)).
Reaction SMILES: [OH:1][C:2]1([CH2:15][NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][C:18]=2[N+:27]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1>[Pt].C(O)C>[NH2:27][C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:17]=1[NH:16][CH2:15][C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:4][CH2:3]1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Agent: [Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CNc2c(N)cnc3ccccc23)CC1

Procedure:
The starting material tert-butyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate (20.23 g, 50.3 mmol) was divided into two portions. To each portion was added ethanol (220 mL) and 5% platinum on carbon (1.1 g). Both portions were hydrogenated on a Parr apparatus at 40 psi (2.8×105 Pa) overnight. The mixtures were filtered through CELITE filter agent. The filtrates were combined and concentrated to provide the product tert-butyl 4-{[(3-aminoquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate as a brown oil. The product was concentrated twice from toluene and once from chloroform and used in the subsequent experiment.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=O.[CH2:13]([Li])CCC.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]([C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[CH2:13]
Reactant: [Li]CCCC
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc([N+](=O)[O-])c1

Procedure:
Treatment of 3-nitroacetophenone (10 g) with methyltriphenyl phosphonium bromide (28 g) and n-butyllithium in hexane (78.4 mmol), as described in Example 1a, gave 3-(1-methylethenyl)nitrobenzene (9.5 g), δ (60 MHz, CDCl3) 2.1 (3H, s, CH3), 5.2 and 5.5 (2H, 2s, CH2), 7.2 to 8.2 (4H, m, ArH). Treatment of the above 3-(1-methylethenyl)nitrobenzene (9.5 g) with hydrogen and palladium on carbon (10%, 1.9 g) as described in Example 1a, gave 3-(1-methylethyl)aniline (6.15 g), δ (60 MHz, CDCl3) 1.1 (6H, d, (CH3)2), 2.6 (1H, m, CH) 3.4 (2H, bs, NH2) and 6.1 to 7.0 (4H, m, ArH).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1>ClCCl>[NH+:12]1([O-:9])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][NH+]1C=Cc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-chloroperbenzoic acid (224.3 g) in dichloromethane (1500 mL) was cooled to 0° C. To this a solution of 1H-pyrrolo[2,3-b]pyridine (59.1 g) in dichloromethane (500 mL) was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated, diluted with methanol (1500 mL) and treated with 10% potassium carbonate in water (300 mL). The slurry was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on neutral alumina with 20% methanol in dichloromethane to give the title compound as a tan solid (47.0 g). MS: 135(MH+). 1HNMR (CDCl3): δ 13.1 (s, 1H), 8.2 (d, 1H), 7.65 (d, 1H), 7.4 (d, 1H), 7.0 (m, 1H), 6.55 (d, 1H).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][Cl:15])=[CH:8][CH:7]=1>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: ClCCCc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(CCCCl)cc1
Temperature: 25 °C

Procedure:
In a 100 ml of round bottomed two-necked flask 4.4 g of NaCN, 18.2 g of 1-(4-chloromethylphenyl)3-chloropropane and 44.8 ml of 90% ethanol are added and boiled at reflux for 5 hours. The feedstock is cooled to room temperature and the precipitate is filtered by suction. The filtrate is concentrated by evaporation. The residue is absorbed in 700 ml of diethyl ether, washed to neutrality with 2×250 ml of distilled water and dried with sodium sulfate. The solution is evaporated to dryness in a rotary evaporator.
Reaction SMILES: C(OC([NH:8][C:9]1[C:19]([CH3:20])=[CH:18][C:12]([O:13][CH2:14][C:15]([OH:17])=O)=[C:11]([CH3:21])[C:10]=1[CH3:22])=O)(C)(C)C.C(OC([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32][CH2:31]1)=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+].FC(F)(F)C(O)=O>CN(C)C=O.C(Cl)Cl.C(N(CC)CC)C>[NH2:8][C:9]1[C:19]([CH3:20])=[CH:18][C:12]([O:13][CH2:14][C:15]([N:36]([CH3:37])[CH:33]2[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]2)=[O:17])=[C:11]([CH3:21])[C:10]=1[CH3:22]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(OCC(=O)O)c(C)c(C)c1NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)N(C)C2CCNCC2)c(C)c(C)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A solution of 1.86 g of 2-[4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenoxy]acetic acid, 1.43 g of 1-(tert-butoxycarbonyl)-4-methylaminopiperidine, 2.94 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP Reagent) and 1.26 ml of triethylamine in 30 ml of dimethylformamide was stirred over night at room temperature. Then, 15 ml of saturated sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated under reduced pressure to give a residue. The obtained residue was dissolved in 30 ml of methylene chloride, and to this solution was added 7.5 ml of trifluoroacetic acid at 0° C., then the mixture was stirred for 2 hours at room temperature. After removal of the solvent, the resultant residue was purified by silica gel column chromatography (methylene chloride:methanol=12:1) to give 1.52 g (81%) of the above-mentioned compound (1).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(O)(C)C.C(=O)=O.C([Li])CCC.[N:26]1([CH2:32][CH:33]2[CH2:36][C:35](=[O:37])[CH2:34]2)[CH2:31][CH2:30][CH2:29][CH2:28]C1>C1COCC1>[N:26]1([CH2:32][CH:33]2[CH2:36][C:35]([C:2]3[CH:13]=[CH:12][C:5]([CH2:6][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:4][CH:3]=3)([OH:37])[CH2:34]2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=C1CC(CN2CCCCC2)C1
Reactant: Brc1ccc(CN2CCCC2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: OC1(c2ccc(CN3CCCC3)cc2)CC(CN2CCCC2)C1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a stirring solution of 1-(4-Bromo-benzyl)-pyrrolidine (Lednicer, Daniel; Lyster, Stanley C.; Duncan, Gordon W. Mammalian antifertility agents. IV. Basic 3,4-dihydronaphthalenes and 1,2,3,4-tetrahydro-1-naphthols. Journal of Medicinal Chemistry (1967), 10(1), 78–84, J. Org. Chem; EN; 46; 17; 1981; 3571–3574) (0.71 g, 2.96 mmol) in THF (13 mL) at −78° C. (isopropanol/CO2) was added a solution of n-butyl lithium (1.6 mL, 3.93 mmol, 2.5 M hexanes). After 15 minutes a pre-cooled (−78 □C) solution of 3-pyrrolidin-1-ylmethyl-cyclobutanone (Intermediate 6, General procedure B Step C) (0.2 g, 1.3 mmol, in 3 mL THF) was added down the side of the flask. After TLC analysis indicated complete consumption of starting material the reaction was quenched cold by the addition of a saturated solution of NH4Cl. The reaction was then warmed to room temperature and diluted with CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were discarded. The aqueous layer was then extracted with 3:1 (CHCl3:isopropyl alcohol) and the combined organic layers were dried over magnesium sulfate, filtered through a fritted funnel, and concentrated under reduced pressure. The material was purified by trituration using ether:hexanes to yield the title compound (0.24 mg, 58% yield) as a colorless solid and a mixture of cis:trans isomers.
Reaction SMILES: ClC1C=C[C:5]([C:8]2[CH:12]3[CH2:13][N:14]([C:16]4[N:25]=[C:24]5[C:19]([C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]5[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[CH:18][C:17]=4[F:38])[CH2:15][CH:11]3[O:10][N:9]=2)=CC=1.C(O)(C(F)(F)F)=[O:40]>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:38])=[C:16]([N:14]3[CH2:15][CH:11]4[CH:12]([C:8]([CH2:5][OH:40])=[N:9][O:10]4)[CH2:13]3)[N:25]=2)[C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O
Reactant: O=C(O)C(F)(F)F
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(CO)C4C3)c(F)cc2c1=O

Procedure:
The title compound was prepared in an analogous manner to acid 101, but using a suitably substituted TFA salt 11. Acid 107 was isolated as a beige solid.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.C(O)C>[C:1]([O:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[NH2:15])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ONC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)ONC(=O)c1cccc(N)c1
Reaction time: 6 h

Procedure:
To an oven-dried 1-L r.b. flask containing 1-tert-butyloxycarbamoyl-3-nitrobenzene (20.0 g, 83.9 mmol) in 500 mL 1:1 ethyl acetate/ethanol at rt was added 10% Pd on C (approx 1 mol %), and the mixture was stirred under an atmosphere of H2 gas for 6 h. The reaction mixture was then filtered, and concentrated under diminished pressure to give 17.4 g (quant of 3-tert-butyloxycarbamoylaniline as a white oily solid. Data for 3-tert-butyloxycarbamoylaniline: 1H NMR (400 MHz, CDCl3) 7.04 (t, J=8.0, 8.0, 1H, 5-H), 6.98 (br s, 1H, NH), 6.53 (dd, J=7.9, 1.8, 1H, 4-H), 6.36 (m, 2H, 6,2-H), 3.66 (br s, 2H, NH2), 1.51 [s, 9H, (CH3)3CO)].
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[Cl:33][C:34]1[CH:39]=[C:38]([N:40]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:37]2[N:57]=[CH:58][C:59](I)=[C:36]2[N:35]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:33][C:34]1[CH:39]=[C:38]([N:40]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:46])[CH3:47])[N:37]2[N:57]=[CH:58][C:59]([C:10]3[CH:9]=[N:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:11]=3)=[C:36]2[N:35]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(I)cnn12
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.38 mmol, 675 mg), K3PO4 (5.96 mmol, 1264 mg), and PdCl2(dppf).CH2Cl2 (0.20 mmol, 162 mg) was added to a solution of 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-10a, 1.98 mmol, 1101 mg) (prepared as described in Step a of Example 10) in dioxane (18 mL) and H2O (3 mL). The resulting solution was stirred at 70° C. under argon overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (x2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded 5-chloro-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-11a): LCMS tR=3.36 Min (5 min run, UV) Mass calculated for, M+581.2, observed LC/MS m/z 582.2 (M+H).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[C:8]([OH:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1.O.O1CCOCC1.Cl[CH:22]([F:24])[F:23]>[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH:22]([F:24])[F:23])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1
Reactant: FC(F)Cl
Reactant: CSc1nc(O)cc(OC(F)F)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(OC(F)F)cc(OC(F)F)n1
Temperature: 40 °C
Yield: 86.7 %

Procedure:
14.0 g (0.067 mole) of 4-difluoromethoxy-6-hydroxy-2-methylthiopyrimidine are suspended in 18 ml of 50% potassium hydroxide solution, 10 ml of water and 160 ml of dioxane. After the addition of 0.5 g of 18-crown-6, the reaction mixture is heated to 40° C., and 20 g of chlorodifluoromethane are subsequently introduced over 5 hours. The aqueous phase is then separated and the organic phase is distilled under a high vacuum, affording 15.0 g (86.4% of theory) of 4,6-bis-difluoromethoxy-2-methylthiopyrimidine with a boiling point of 63° C./0.06 mbar. The substance melts at 46°-48° C.
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:20]=[CH:19][C:10]([CH:11]=[C:12]2[S:16][C:15](=[S:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)([CH3:3])[CH3:2].CI.[CH:27](N(C(C)C)CC)(C)C.O>C(O)C>[CH:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:20]=[CH:19][C:10]([CH:11]=[C:12]2[S:16][C:15]([S:17][CH3:27])=[N:14][C:13]2=[O:18])=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1Oc1ccc(C=C2SC(=S)NC2=O)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CI
Solvent: CCO
Product: CSC1=NC(=O)C(=Cc2ccc(Oc3ccccc3C(C)C)cc2)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
To a solution of 5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-thioxo-thiazolidin-4-one (0.4 g, 1.12 mmol) in Ethanol (14 mL) was added CH3I (0.32 g, 2.25 mmol) and diisopropylethylamine (0.17 g, 1.35 mmol). The reaction mixture was stirred at room temperature for 4 h. It was then added water (40 mL) and the slurry was stirred at room temperature for 30 minutes. The solid was filtered, washed with water to yield the 5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one as a yellow solid (0.42 g, 94%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[CH:13]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:18]2[CH2:19][CH2:20][N:21]([C:2]3[CH:7]=[C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=3)[CH2:22][CH2:23]2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC(=O)N(C)c1ccnc(Cl)c1
Reactant: C1CCC(N2CCNCC2)C1
Product: CC(=O)N(C)c1ccnc(N2CCN(C3CCCC3)CC2)c1
Temperature: 120 °C

Procedure:
A mixture of 4 g (22 mmol) N-(2-chloro-pyridin-4-yl)-N-methyl-acetamide and 3.5 g (23 mmol) 1-(cyclopentyl)-piperazine was heated to 120° C. for 24 h. The crude product was purified by flash column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate (0.1% NEt3) to yield after evaporation of the product fractions 3.3 g (50%) of the title compound as light brow oil. MS: (m/e): 303.3 (MH+).