Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10]I>O1CCCC1>[CH3:10][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: CI
Solvent: C1CCOC1
Product: CNc1ccc(C#N)cc1
Yield: 76 %

Procedure:
This compound was prepared by treating 4-aminobenzonitrile with a slight excess, on a molar equivalents basis, of methyl iodide in tetrahydrofuran solvent for 4 hrs at room temperature. Removal of the THF and other volatiles, followed by recrystallization, gave a 76% yield of 4-(N-methyl)aminobenzonitrile, mp 85-87° C. Using Example 1 procedure, the aforesaid substituted nitrile was treated with ethanolamine to obtain a 70% yield of 2-[4-(N-methyl)aminophenyl]oxazoline, mp 145-147° C. Following the Example 6 procedure, the aforesaid compound was treated with TDO to form the oxazoline shown below, having a methyl group attached to the nitrogen in the acetoacetanilide segment. The product was recrystallized from ethyl acetate, mp 102-105° C. Elemental analysis, FT-IR, exhibiting 1726 (C—O) and 1635 (—C═N—) cm−1 absorptions, and with 1H NMR confirmed the below drawn structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[C:9]=1[N+:15]([O-:17])=[O:16].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[NH2:14][C:10]1[C:9]([N+:15]([O-:17])=[O:16])=[C:8]([O:7][C:6]2[C:5]([Cl:19])=[CH:4][C:3]([Cl:20])=[C:2]([NH:1][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=3)=[O:30])[CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])c(Cl)cc1Cl
Product: Nc1nccc(Oc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 73 %

Procedure:
Method G was used with 4-(5-amino-2,4-dichlorophenoxy)-2-amino-3-nitropyridine and 4-chloro-3-trifluoromethylphenyl isocyanate to afford the title compound as a yellow powder (740 mg, 73%). 1H-NMR (δ, ppm, DMSO-d6): 6.01 (d, 1H, HPy,5, J=5.6 Hz), 7.26 (s, 2H, NH2,Py), 7.62 (m, 2H, Harom), 7.90 (s, 1H, Harom), 8.03 (m, 2H, Harom+HPy6), 8.21 (s, 1H, Harom), 8.63 (s, 1H, NHurea), 9.95 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 99.7 (C-4); 114.1 (C-11); 116.8 (C-); 116.9 (C-); 118.7 (C-); 119.7 (C-); 121.1 (C-); 123.1 (C-); 123.2 (C-); 123.8 (C-); 130.5 (C-); 132.2 (C-); 136.2 (C-10 or 13); 138.5 (C-10 or 13); 147.4 (C-6); 151.7 (C-12); 153.4 (C-5); 153.9 (C-1); 157.6 (C-3). LC-MS (m/z): 535 (M+H, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: Cc1ccc(Oc2cccc(CO)c2)nc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Oc2cccc(CCl)c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
(3-(5-Methylpyridin-2-yloxy)phenyl)methanol from Step 1 (1.9 g, 8.8 mmol), in dichloromethane (25 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (0.773 mL, 10.6 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was stirred at RT for 5 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated by evaporation to afford the title compound (2.1 g, 99% yield) as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][C:19]([OH:21])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][C:19](=[O:21])[C:9]=2[CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Sc2ccccc2CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc2c(c1)C(=O)Cc1ccccc1S2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1.0 g of 2-(4-methylsulfonylphenylthio)phenylacetic acid and 10 ml of polyphosphoric acid under nitrogen is stirred at 90°-100° C. for 2 hours. The reaction mixture is permitted to cool and then poured into 100 ml of an ice-water slurry. The aqueous solution is basified with 20% sodium hydroxide before being extracted with methylene chloride. The combined extracts are dried and then evaporated to dryness leaving an oil. The oil is chromatographed through a silica gel column with a 2% methanol in methylene chloride eluant. The chromatographed solution is evaporated to dryness providing 10,11-dihydro-2-methylsulfonyl-11-oxodibenzo[b,f]thiepin.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CO.[Zn]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:12]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
A solution of N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)acetamide (1.48 g, 5.40 mmol) and NH4Cl (7.22 g, 135 mmol) in MeOH (25 mL) was treated with zinc (2.82 g, 43.2 mmol) and stirred at RT for 1 h. The solids were removed via filtration through diatomaceous earth, washed with MeOH and the filtrate concentrated to near-dryness. The residue was treated with water, extracted with EtOAc (2×) and the combined organics were washed with brined, dried over Na2SO4 and concentrated to dryness. The material was treated with 60% EtOAc/Hex, the solid collected via filtration, washed with 60% EtOAc/Hex and dried to afford N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)acetamide (750 mg, 57%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 8.11 (d, J=5.7 Hz, 1H), 7.76 (d, J=2.9 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.24 (dd, J=8.9, 3.0 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H), 6.49 (d, J=8.9 Hz, 1H), 6.00 (s, 2H), 2.01 (s, 3H); MS (ESI) m/z: 245.1 (M+H+).
Reaction SMILES: C(OC([C:6]1([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])=O)C.Br>O1CCOCC1>[O:11]=[C:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH3:25])[C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)c1ccc(CC2(C(=O)OCC)CCCC2=O)cc1
Agent: Br
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc(CC2CCCC2=O)cc1
Yield: 92.1 %

Procedure:
Twenty grams of ethyl 2-[4-(1-ethoxycarbonyl-2-oxocyclopentan-1-ylmethyl)phenyl]propionate was dissolved in 30 ml of dioxane and 100 ml of 47% hydrobromic acid and the solution was refluxed for 6 hours. The reaction mixture was then extracted with ether, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give an yellow oily substance. The product was subjected to a vacuum distillation to yield 13.1 g of the desired compound as a colorless oily substance, b.p. 190°-195° C. at 0.3 mm Hg (bath temp.). The compound solidified as it was cooled to crystals, m.p. 108.5°-111° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]([N:26]5[CH2:30][CH:29]([O:31][CH3:32])[CH2:28][CH:27]5[C:33](C)(C)[O:34][SiH2]C(C)(C)C)=[O:25])[S:23][C:16]=34)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:42])=[O:4].C(O)(C(F)(F)F)=O>C(O)(=O)C.C1COCC1>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]([N:26]5[CH2:30][CH:29]([O:31][CH3:32])[CH2:28][CH:27]5[CH2:33][OH:34])=[O:25])[S:23][C:16]=34)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:42])=[O:4]
Reactant: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)N5CC(OC)CC5C(C)(C)O[SiH2]C(C)(C)C)sc34)ccc21
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)N5CC(OC)CC5CO)sc34)ccc21

Procedure:
Example 3(o) was prepared by dissolving the starting material 5-{2-[2-(tert -Butyl-dimethyl-silanyloxymethyl)-4-methoxy-pyrrolidine-1-carbonyl]-thieno[3,2-b]pyridin-7-yloxy}-2-methyl-indole-1-carboxylic acid methylamide (0.55 g, 1.00 mmol), as prepared in step i below, in 1 mL of acetic acid in 0.5 mL of THF and 0.5 mL of TFA and stirring at 50° C. for 3 h. The reaction mixture was quenched with 5 mL of sat. NaHCO3 and 50 mL of EtOAc the partitioned with 50/50 NaHCO3 (2×50 mL) organic layer dried over NaSO4 and concentrated. The residue purified with a 2 mm choromatotron rotor eluting with EtOAc/CH2Cl2/MeOH (2:1:0.2) then combining purified fractions. The product was then crashing out of EtOAc and diethyl ether producing 0.34 g (68.5%) of 5-[2-(2-Hydroxymethyl-4-methoxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-indole-1-carboxylic acid methylamide as white solid. HPLC: Rt 5.06 min. (94% area). 1H NMR (CDCl3, 400 MHz) δ: 8.50 (1H, d, J=5.3 Hz), 7.81 (1H, s), 7.71 (1H, d, J=9.0), 7.30 (1H, s), 7.03 (1H, d, J=6.9 Hz), 6.60 (1H, d, J=5.3 Hz), 6.33 (1H, s), 5.69 (1H, bs), 4.57 (1H, q, J=6.8 Hz), 4.33 (1H, s), 4.08 (1H, d, J=11.6 Hz), 4.00 (1H, s), 3.86 (2H, t, J=11.6 Hz), 3.85-3.75 (1H, m), 3.28 (3H, d, J=4.3 Hz), 2.61 (3H, s), 2.34-2.29 (1H, m). HRMS (ESI) C25H27N4O5S2 (M+H+) m/z: Calc. 495.1702, Found: 495.1704. Anal. (C25H26N4O5S2.0.2 EtOAc) Calc'd: C, 60.50; H, 5.43; N, 10.94; Found: C, 60.73; H, 5.61; N, 10.10.86.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[CH2:26][N:25](CC5C=CC(OC)=CC=5)[C:24]4=[O:38])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[CH2:26][NH:25][C:24]4=[O:38])=[CH:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.9 %

Procedure:
3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (105 mg) described in Example 420 was dissolved in dichloromethane (1 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, 5% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform/methanol (10/1). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was suspension washing with IPE to give the title compound (86 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:17](=[O:18])[C:16]([F:23])([F:22])[F:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNC(=O)C(F)(F)F
Reaction time: 3 h
Yield: 100.4 %

Procedure:
(S)-2-aminomethyl-pyrrolidine-l-carboxylic acid tert-butyl ester (10 g, 49.93 mmol) was dissolved in THF (200 ml) followed by the dropwise addition, within 5 min, of ethyl trifluoroacetate (9.75 g, 67.95 mmol) dissolved in THF (50 ml). Stirring was continued for 3 h at RT. The reaction mixture was concentrated under reduced pressure and the residue dried at HV to give the expected compound (14.86 g). LC-MS: tR=0.93 min; [M+H]−=297.29.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(CS(C)(=O)=O)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)Cc1ccc(C(=O)O)c(Cl)c1

Procedure:
3.01 g of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted via Procedure O to give tert-butyl 2-chloro-4-(methylsulfonylmethyl)benzoate. 1.2 g of tert-butyl 2-chloro-4-(methylsulfonylmethyl)benzoate was treated with 10 mL of 4N HCl in Dioxane at 45° C. and concentrated upon completion to give crude 2-chloro-4-(methylsulfonylmethyl)benzoic acid. 775 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1 g of 2-chloro-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 435 (M)+.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][OH:13].CCN(CC)CC>C1COCC1>[OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:3]1
Reactant: OC1CNCC12CC2
Reactant: OCCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.5 %

Procedure:
To a solution of 7-hydroxy-5-azaspiro[2.4]heptane (1.23 g, 11.0 mmol) in THF (40 mL) was added 3-bromopropanol (2.3 g, 16.65 mmol) and Et3N (2.24 g, 22.2 mmol). The reaction mixture was stirred at rt for 12 hrs and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:50:2(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as orange oil (1.14 g, 60%).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:14])=[N+:2]=[N-:3].[Se](=O)=[O:16]>>[N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:16])[C:9]2=[O:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cccc2c1CCCC2=O
Reactant: O=[Se]=O
Product: [N-]=[N+]=Nc1cccc2c1C=CC(=O)C2=O

Procedure:
Treatment of 5-azido-1-tetralone with selenium dioxide as described in Reference Example 1A yielded 5-azido-[1,2]naphthoquinone which was coupled with 2,3-diamino-benzoic acid, diacetate salt, as described in Reference Example 1A to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:22]=[CH:21][N:13]3[C:14](=[O:20])[C:15]([CH:18]=[CH2:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C([OH:25])C>>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:22]=[CH:21][N:13]3[C:14](=[O:20])[C:15]([CH:18]([OH:25])[CH3:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: C=Cc1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Product: CC(O)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8-((3-fluorophenyl)ethynyl)-3-vinyl-4H-pyrido[1,2-a]pyrimidin-4-one (30 mg, 0.1 mmol) was added into a saturated HO/ethanol (5 mL) solution. After stirring at ambient temperature for 3 h, the solution was adjusted to pH=8 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography. MS (ESI): 309 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.01-8.99 (d, J=7.44 Hz, 1H), 8.38 (s, 1H), 7.77 (s, 1H), 7.45-7.39 (m, 2H), 7.33-7.28 (m, 1H), 7.20 (m, 1H), 7.17 (m, 1H), 5.11-5.02 (m, 1H), 3.54-3.52 (d, J=6.03 Hz, 1H), 2.62-2.57 (d, J=6.6 Hz, 3H). mGluR5 PAM EC50: ++. Fold shift at 10 μM: +.
Reaction SMILES: C([Mg]Br)C.[CH:5]1([C:8]#[CH:9])[CH2:7][CH2:6]1.[N:10]([C:13]1[S:14][C:15]2[CH2:16][CH2:17][O:18][C:19]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:20]=3[C:21]=2[N:22]=1)=[N+:11]=[N-:12]>C1COCC1>[Br:27][C:25]1[CH:24]=[CH:23][C:20]2[C:21]3[N:22]=[C:13]([N:10]4[C:8]([CH:5]5[CH2:7][CH2:6]5)=[CH:9][N:12]=[N:11]4)[S:14][C:15]=3[CH2:16][CH2:17][O:18][C:19]=2[CH:26]=1
Reactant: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: C#CC1CC1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCc1sc(-n3nncc3C3CC3)nc1-2
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a 1M solution of ethylmagnesium bromide in THF (1.3 mL, 1.3 mmol) under a nitrogen atmosphere, was added dropwise cyclopropylethyne (70% in toluene, 0.154 mL, 1.3 mmol). The reaction mixture was heated at 50° C. for 15 mins then allowed to cool down to RT. A solution of 2-azido-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (425 mg, 1.3 mmol) in THF (1.5 mL) was then added dropwise. The reaction mixture was stirred at RT for 2 h, quenched with aqueous saturated ammonium chloride and diluted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was triturated with 20% ethyl acetate/cyclohexane and filtered to afford the title compound as a pale yellow solid (373 mg, 64%). LCMS 110142391 (Method B): RT=4.40 min, [M+H]+=390. 1H NMR (DMSO-d6): 8.20 (1 H, d, J=8.6 Hz), 7.71 (1 H, d, J=0.7 Hz), 7.36 (1 H, dd, J=8.6, 2.1 Hz), 7.30 (1 H, d, J=2.1 Hz), 4.40 (2 H, t, J=5.0 Hz), 3.41 (2 H, t, J=5.0 Hz), 2.70-2.63 (1 H, m), 1.21-1.15 (2 H, m), 0.91-0.86 (2 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][S:17][C:10]=2[N:11]=[C:12]([NH:15][NH2:16])[CH2:13][N:14]=1.C(=O)(O)[O-].[Na+].[C:25](Cl)(=O)[CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][S:17][C:10]=2[N:11]2[C:25]([CH3:26])=[N:16][N:15]=[C:12]2[CH2:13][N:14]=1
Reactant: CC(=O)Cl
Reactant: NNC1=Nc2sccc2C(c2ccccc2Cl)=NC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnc2n1-c1sccc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2 g (0.0069 mol) of 5-(o-chlorophenyl)-2-hydrazino-3H-thieno[2,3-e]-1,4-diazepine are suspended in 200 ml of dry methylene chloride and treated with 10 g of sodium bicarbonate. The solution is cooled to 0° C. and treated with stirring with 0.8 ml of acetyl chloride. After 45 minutes, the solid material is filtered off from the solution which is then shaken out twice with 100 ml of water each time. After drying over sodium sulphate, the organic phase is evaporated and treated with 100 ml of butanol, whereupon 20 ml thereof are evaporated off under reduced pressure. The solution is refluxed for 8 hours and evaporated under vacuum. After trituration of the oily residue with ethanol, the resulting crystals are refluxed with a small amount of ethanol, left to crystallize in a refrigerator, filtered under a vacuum and dried to yield 4-(o-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 221°-223° C.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:31][S:32]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:38]4[CH2:39][CH2:40][CH:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Agent: Cl
Product: CS(=O)(=O)C1CCN(c2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cn2)CC1

Procedure:
4-Methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and 4-methanesulfonyl piperidine hydrochloride. MS calcd. for C28H27ClN4O4S [(M+H)+] 551.1, obsd. 551.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: COc1cccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1cccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)c1

Procedure:
Treatment of (±)-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.0 g, 7.82 mmol) with sodium azide (0.309 g, 4.48 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.030 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.25 g (80%) of (±)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 152-154° C.; Anal. calcd. for C16H17NO2HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 65.21; H, 6.17; N, 4.46.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:4].[F:13][C:14]1[CH:15]=[C:16]([N:33]2[CH2:37][C@H:36]([CH2:38][N:39]3[CH:43]=[CH:42][N:41]=[N:40]3)[O:35][C:34]2=[O:44])[CH:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH2:30][C@@H:29]([CH2:31]O)[O:28][N:27]=2)=[CH:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:31][C@H:29]1[O:28][N:27]=[C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[CH:18]=[CH:17][C:16]([N:33]4[CH2:37][C@H:36]([CH2:38][N:39]5[CH:43]=[CH:42][N:41]=[N:40]5)[O:35][C:34]4=[O:44])=[CH:15][C:14]=3[F:13])=[CH:21][N:22]=2)[CH2:30]1)=[O:11])=[O:4]
Reactant: COC(=O)NCCCCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NCCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The methyl carbamate prepared as above (0.25 g, 1.43 mmol), (5R)-3-(3-fluoro-4-{6-[(5S) -5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white powder (0.33 g), melting point: 90° C.