Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])[N:17]=1)[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])[CH3:2].[CH2:25]([NH:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:16]1[CH:21]=[C:20]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH3:31])[N:19]=[C:18]([CH3:23])[N:17]=1)[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])[CH3:2]
Reactant: CCCCNCC
Reactant: CCOC(=O)CN(c1cc(Cl)nc(C)n1)c1c(C)cc(C)cc1C
Solvent: CS(C)=O
Product: CCCCN(CC)c1cc(N(CC(=O)OCC)c2c(C)cc(C)cc2C)nc(C)n1
Temperature: 135 °C
Yield: 122.2 %

Procedure:
A mixture of [(6-chloro-2-methyl-pyrimidin-4-yl)(2,4,6-trimethylphenyl)-amino]-acetic acid ethyl ester (85 mg, 0.244 mmol) and N-butyl-ethylamine (0.17 ml, 1.1 mmol) in 4 ml DMSO was heated at 135° C. for 15 hours. An additional 1 ml of N-butylethylamine was added and the reaction was heated at that temperature for an additional 15 hours (tlc showed no starting material). The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 123 mg of a light amber oil. The oil was purified through silica gel chromatotron using 5% ethyl acetate in hexane as eluent to give 92 mg (91%) of the title compound as a white glass. 1H NMR (CDCl3) δ 6.94 (s, 2H), 4.69 (s, 1H), 4.23 5,<; (s, 2H), 4.22 (q, 2H), 3.35 (q, 2H), 3.15 (t, 2H), 2.36 (s, 3H), 2.31 (s, 3H), 2.21 (s, 6H). 1.3-1.5 (m, 2H), 1.34 (tL 3H), 1.1-1.3 (m, 2H), 1.01 (t. 3H), 0.80 (t, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[NH:9]1[CH2:8][CH2:7][C:6]2([C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:3]([C:1]#[N:2])=[CH:4][CH2:5]2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC=C(C#N)c3ccccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1=CCC2(CCNCC2)c2ccccc21

Procedure:
A solution of the nitrile (A3) (300 mg) in dichloromethane (3 ml) was treated with TFA (1 ml) for 1 hour, concentrated, co-evaporated with acetonitrile and dissolved in dichloromethane (ca. 100 ml). The resulting solution was washed with a mixture of brine (ca. 20 ml) and 6N NaOH (2 ml), dried over Na2SO4, and concentrated to give 2H-spiro[naphthalene-1,4′-piperidine]-4-carbonitrile (A4) as a white solid. LC-MS: m/e=225.2 (M+H). Rt=1.53 min.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:18][C:19](=O)[NH:20][C:21]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:22]=4[C:23]=3[N:24]=2)[C:9]([CH3:12])=[N:10][CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:18][C:19](=[S:36])[NH:20][C:21]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:22]=4[C:23]=3[N:24]=2)[C:9]([CH3:12])=[N:10][CH:11]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1ncc(CCCN(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ncc(CCCN(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=S)C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of 2-({5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (175 g, 372 mmol), phosphorus pentasulfide (82.7 g, 372 mmol) and pyridine (1.35 L) was heated at 50° C. for 18 hours. HPLC analysis showed completion of the reaction. After the reaction mixture was cooled below room temperature, a solution of sodium carbonate (525 g, 4.95 mol) in 5.1 L of water was slowly added while the temperature was kept at below room temperature. The resulting biphasic solution was separated and the organic layer was washed with the same amount of sodium carbonate solution two times. The organic phase was then reduced to ca. 1.1 L in volume. The solution was diluted with water (1.0 L) and stirred at room temperature overnight resulting in a yellow suspension. The solid was filtered and washed with 200 mL EtOH/water (1 vol/2 vol), and water 200 mL. After drying overnight under vacuo at 40° C., the crude product was dissolved in 1.2 L of EtOH at reflux. Water (2.0 L) was slowly added at 75° C. to induce crystallization. The suspension was then slowly cooled to room temperature and stirred overnight. The solid 2-({5-[3-(Dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thione was filtered and dried under vac at 40° C. to a constant weight (140.0 g, HPLC purity>98%, 77% yield). LCMS (FA): Rt=6.26 min, m/z=485.2 (M−H).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH:6]([O:9]C(C)C)(C)[CH3:7].Cl[CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:7][CH2:6][O:9][Si:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)OC(C)C
Reactant: ClCCl
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)OCCCCl

Procedure:
A solution of chlorotrimethylsilane (126.40 g, 1.164 mol) in dichloromethane (300 L) is then added dropwise maintaining the temperature between 0° C. and 5° C. When the conversion is complete, diisopropyl ether (600 mL) is added and triethylamine hydrochloride is filtered washing the pad with diisopropyl ether. The filtrate is concentrated at 38° C. under reduced pressure and the product is purified by distillation (0-5 mmHg, 70° C.). (3-Chloropropoxy)trimethylsilane is obtained as a colourless liquid (144.57 g, 0.867 mol, 82%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:32]1([CH2:38][CH2:39][S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:46][C:45]1[CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[O:16][C:42](=[O:43])[C:41]=1[S:40][CH2:39][CH2:38][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)c1cccc(Oc2ccccc2)c1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2cccc(Oc3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-phenoxyacetophenone (2.00 g, 9.43 mmol), lithium bis(trimethylsilyl)amide (2.36 g, 14.15 mmol), chlorotrimethylsilane (1.79 mL, 14.15 mmol), THF (100 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. 114-115° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 2.99 (t, 2 H), 6.76 (s, 1 H), 7.09 (m, 7 H), 7.34 (s, 1 H), 7.44 (t, 2 H), 7.56 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][O:14][C:13]2[CH:16]=[C:17](C)[CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:21].C(OC(N[C@@H](CO)C(O)=O)=O)(C)(C)C.FC1C=CC([C:43]([F:46])([F:45])[F:44])=CC=1[N+]([O-])=O>CCCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([C:43]([F:46])([F:45])[F:44])=[CH:19][C:12]=2[NH:11][C:10]1=[O:21]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Agent: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: N[C@H]1COc2ccc(C(F)(F)F)cc2NC1=O

Procedure:
In a similar manner to that described for the preparation of (S)-3-amino-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate except in Step 3 the reaction mixture was stirred for 4 h and in the material obtained in Step 4 was triturated with hexane, (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (4.1 g, 20.0 mmol) and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (4.18 g, 20.0 mmol) were converted to the title compound (1.06 g) which was used without purification.
Reaction SMILES: CN.[C:3]([O:7][C:8](=[O:23])[NH:9][CH2:10][CH:11]1[CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12]1)([CH3:6])([CH3:5])[CH3:4].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[Pd]>[C:3]([O:7][C:8](=[O:23])[NH2:9])([CH3:6])([CH3:5])[CH3:4].[CH3:8][NH:9][CH2:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: CN
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: CC(C)(C)OC(N)=O
Product: CNCC1CCNC1
Yield: 92 %

Procedure:
To a solution of (1-benzyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester methyl amine (1.0 g, 3.28 mmol) in methanol (35 ml) was added Pd/C (20%) (0.22 g). The resulting mixture was hydrogenated at 50 Psi over night. The Pd was filtered over Celite and evaporated to dryness to give the desired product in 92% yield.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7].CC(C)=O>O>[N:1]([S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7])=[N+:2]=[N-:3]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NS(=O)(=O)c1cccc(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
In a three-necked flask fitted with stirrer and dropping funnel 65 g of sodium azide is dissolved in 900 ccs of water. While stirring and cooling till 0°-5° C a solution of 198 g of m-chlorosulphonyl-benzoic acid in 900 ccs of acetone is added dropwise. Then stirring is continued for 30 minutes whereupon the solution obtained is poured into 2 liters of water. The white precipitate formed is sucked off, washed with water and dried in vacuo. Melting point: 143° C.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][C:18]#[C:19][CH2:20][CH2:21][CH3:22].C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: CCCC#COc1cc(C=O)ccc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C#CCCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 75.3 %

Procedure:
Piperidine (0.45 mL, 4.6 mmol) was added to a suspension of 4-methoxy-3-(pent-1-ynyloxy)benzaldehyde (1.0 g, 4.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.93 g, 4.2 mmol) in toluene (10 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(4-methoxy-3-(pent-4-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.2 g, 77%) as a yellow crystalline solid; mp 154-156° C.; δH (400 MHz, DMSO-d6) 1.91 (p, 7.6 Hz, 2H, CH2), 2.34 (dt, J=7.6, 2.4 Hz, 2H, CH2CCH), 2.82 (t, J=2.4 Hz, 1H, CCH), 3.80 (s, 3H, OCH3), 4.10 (t, J=7.6 Hz, 2H, OCH2), 6.78 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.26 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 14.5, 27.8, 55.6, 66.8, 71.6, 83.8, 111.7, 111.8, 116.6, 119.9, 120.3, 122.6, 122.8, 127.2, 131.1, 134.0, 141.1, 141.6, 148.1, 150.9, 164.1, 169.4; HRMS (ESI) calculated for C22H21NO5 [M+H]+ 380.1492. found 380.1490; vmax 754, 1257, 1510, 1584, 1659, 2944, 3250, 3512 cm−1.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([N+:17]([O-:19])=[O:18])=[C:5]([O:20][C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:4]=1.[S:37](S([O-])=O)([O-:40])(=O)=[O:38].[K+].[K+].[CH3:46]O>O1CCOCC1.O>[CH3:46][S:37]([C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([N+:17]([O-:19])=[O:18])=[C:5]([O:20][C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:4]=1)(=[O:40])=[O:38]
Reactant: CO
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CSc1nc(NCc2ccccc2)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1nc(NCc2ccccc2)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 2-methylthio-4-benzylamino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine (1.82 g, 3.76 mmol) in 40 mL MeOH and 40 mL dioxane at 0° C. was added potassium metabisulfite (KHSO5) (3.59 g, 11.3 mmol) in 40 mL water. The suspension was allowed to warm to ambient temperature and stirred for 15 hours. The reaction was concentrated to 25 mL and extracted with methylene chloride (200 mL). The organic layer was dried (Na2 SO4), evaporated and chromatographed on silica gel (2:1, hexane/ethyl acetate) to afford 0.26 g of 2-methylsulfonyl-4-benzylamino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (F), as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N+:13]([C:16]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:17]=1[NH2:18])([O-:15])=[O:14].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O>[CH3:7][NH:6][C:5]1[CH:8]=[CH:9][C:2]([C:21]2[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:13]([O-:15])=[O:14])[CH:22]=2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O
Solvent: COCCOC
Product: CNc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 169.4 %

Procedure:
4-Bromo-N-methyl-2-nitroaniline (100 mg, 0.43 mmol), 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (115 mg, 0.43 mmol), biphenyl-2-yldicyclohexylphosphine (30 mg, 20 mol %) and K3PO4 (275 mg, 1.3 mmol) were suspended in DME-H2O (4:1, 5 mL). the mixture was purged with nitrogen then degassed by sonication. Pd(OAc)2 (5 mg, 5 mol %) was added, and the mixture heated to 130° C. for 10 min under microwave irradiation. The cooled mixture was diluted with EtOAc and H2O. The organics were separated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a dark brown solid (210 mg). The crude material was taken on without further purification.
Reaction SMILES: C(NC([O:8][CH2:9][CH3:10])=O)CCC.C(NC(OCC)=O)CCC.[CH2:21](O)[C:22]#[C:23][C:24]#[C:25][CH2:26][OH:27].C(NC(OCC)=O)C.C(NC(OCC)=O)C.C(O)C#CC#CCO>>[CH2:9]([OH:8])[CH2:10][C:21]#[C:22][C:23]#[C:24][CH2:25][CH2:26][OH:27]
Reactant: CCCCNC(=O)OCC
Reactant: OCC#CC#CCO
Agent: CCNC(=O)OCC
Product: OCCC#CC#CCCO

Procedure:
2,4-hexadiyn-1,6-diol bis(n-butylurethane) plus 2,4-hexdiyn-1,6-diol bis(ethylurethane)
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](=[O:12])([O-])[O-].[K+].[K+].Cl[C:16]1[CH:30]=[CH:29][C:19]([C:20]([C:22]2[CH:27]=[CH:26][C:25](Cl)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.Cl>CN(C=O)C.O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:16]2[CH:30]=[CH:29][C:19]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([S:1][C:2]4[CH:7]=[CH:6][C:9]([OH:12])=[CH:4][CH:3]=4)=[CH:24][CH:23]=3)=[O:21])=[CH:18][CH:17]=2)=[CH:3][CH:4]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Oc1ccc(S)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Sc2ccc(O)cc2)cc1)c1ccc(Sc2ccc(O)cc2)cc1
Temperature: 80 °C
Yield: 86 %

Procedure:
A mixture of 4-mercaptophenol (50g, 0.317 mol for 80% purity), anhydrous potassium carbonate (46.9 9, g. 0.34 mol) and 150 mL of DMF was stirred and heated under nitrogen at 110°-120° C. for 90 min. The mixture was cooled to 80° C., a suspension of 4,4'-dichloro-benzophenone (40.1 g, 0.16 mol) in 100 mL DMF was added over 5 min and the mixture was stirred and heated under reflux for 4 h. After cooling to room temperature, there was added 400 mL of water and enough conc. HCl to adjust the pH to ca. 2. After stirring for 1 h, the pale yellow solid was filtered, washed with water and recrystallized from aqueous ethanol to afford 4,4'-bis(4-hydroxyphenylthio)benzo-phenone as pale yellow microcrystals, 59 g (86% yield), mp 219°-221° C. 1H NMR (DMSO-d6) was consistent with the structure with a sharp singlet for OH at δ 10.02 and four sets of doublets for the aromatic protons ranging from δ 7.61 to 6.99.
Reaction SMILES: [OH2:1].O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:22]1[CH:29]2[CH:23]1[CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:28]=12.[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([Si](C)(C)C)=[N:42][CH:43]=1>>[N+:34]([C:31]1[CH:32]=[CH:33][C:27]2[O:26][CH2:25][CH2:24][C@@H:23]([OH:22])[C@H:29]([N:42]3[CH:43]=[C:38]([Cl:37])[CH:39]=[CH:40][C:41]3=[O:1])[C:28]=2[CH:30]=1)([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1OC1CCO2
Reactant: O
Reactant: C[Si](C)(C)c1ccc(Cl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=c1ccc(Cl)cn1[C@@H]1c2cc([N+](=O)[O-])ccc2OCC[C@H]1O
Temperature: 60 °C

Procedure:
6.63 g (21 mmol) of tetrabutylammonium fluoride trihydrate are added to a stirred mixture of 3.93 g (19 mmol) of 4,5-epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepin and 8.06 g (40 mmol) of 5-chloro-2-trimethylsilyl-pyridine, and the mixture is heated at 60° C. for 5 hours. The mixture is then stirred into ice-water and extracted several times with ethyl acetate. The combined ethyl acetate extracts are washed with water and saturated sodium chloride solution dried over sodium sulfate, filtered and evaporated in vacuo. The remaining viscous oil crystallizes after standing for some time. It is triturated with ethyl acetate and filtered off with suction. Crystals of melting point 219°-222° C. are obtained.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:5]([Li])[CH2:6][CH2:7][CH3:8].CN(CCN(C)C)C>CCCCCC>[CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Li]CCCC
Agent: C=CC=C
Agent: CN(C)CCN(C)C
Solvent: CCCCCC
Product: C=Cc1ccccc1
Temperature: 88 °C
Reaction time: 0.51 h

Procedure:
In this experiment, a styrene-butadiene polymer was synthesized utilizing the continuous polymerization procedure described in U.S. Pat. No. 5,837,756. A two-reactor system which consisted of a 1-gallon first reactor and a 2-gallon second reactor was utilized with the polymerization temperature being maintained at about 190° F. (88° C.). In the procedure used, 1,3-butadiene was charged into the first reactor at a rate of 115.2 grams per minute, n-butyl lithium was charged into the first reactor as a 0.25 M solution at a rate of 1.6 grams per minute and TMEDA was charged into the first reactor as a 0.25 M solution at a rate of 1.04 grams per minute. The 1,3-butadiene monomer was charged into the reactor as a 16 weight percent premix solution in hexane. The residence time in the first reactor was 0.51 hours.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([CH2:16][CH:17]([N:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[N:22][CH2:21]2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([N:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[N:22][CH2:21]1)[CH2:16][C:13]1([F:12])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1(F)CC1)N1C=CC(C(F)(F)F)=NC1
Product: O=C(NCC(CC1(F)CC1)N1C=CC(C(F)(F)F)=NC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-(1-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS (MH+): m/z=436.1, tR (minutes, Method G)=2.61
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH2:30]1[N:35]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:34][CH2:33][O:32][CH2:31]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:42][C:39]3[CH:38]=[CH:37][C:36]([N:35]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:41][CH:40]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Yield: 7.2 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 4-(4-morpholino)aniline (0.155 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and The reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 12.51 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine as a lyophilized powder. (M+H)=402.8. 1H NMR (400 MHz, DMSO, d6) δ 9.23 (m, 1H), 8.91 (s, 1H), 7.81 (dd, 1H, J=1.60, 6.01 Hz), 7.62 (d, 2H, J=8.88 Hz), 7.45 (m, 1H), 7.21 (d, 1H, J=8.13 Hz), 7.12 (t, 1H, J=7.60 Hz), 6.91 (m, 4H), 3.80 (s, 3H), 3.75 (m, 4H), 3.09 (m, 4H).
Reaction SMILES: [I-].[C:2]([O:6][C:7]([NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)=[O:16])[CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[N:27][C:28]2CCNC[C:33]=2[CH:34]=1.CCN(CC)CC>C(Cl)Cl>[C:2]([O:6][C:7](=[O:8])[NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH2:18][CH2:33][C:28]3[N:27]=[CH:26][C:25]([C:24]([F:36])([F:35])[F:23])=[CH:34][C:20]=3[CH2:21]2)=[O:16])[CH2:11]1)([CH3:3])([CH3:4])[CH3:5]
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: C[n+]1ccn(C(=O)N2CCC(NC(=O)OC(C)(C)C)C2)c1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of 3-(3-tert-butoxycarbonylamino-pyrrolidine-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (preparation #4) (7.81 g, 18.5 mmol) in DCM (70 mL) was added 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine (3.74 g, 18.5 mmol) and Et3N (2.6 mL, 18.5 mmol) and the reaction mixture was stirred at ambient temperature for about 16 h. Additional Et3N (1.5 mL, 10.7 mmol) was added and the reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 5% MeOH/DCM as the mobile phase to give [1-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridine-6-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (4.91 g, 64%). RP-HPLC (Table 1, Method a) Rt 2.37 min; m/z: (M+H)+ 415.