Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:35][CH2:34][CH2:33][S:32]1(=[O:37])=[O:36]>>[O:36]=[S:32]1(=[O:37])[CH2:33][CH2:34][CH2:35][N:31]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: O=S1(=O)CCCN1c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3N3CCCS3(=O)=O)cc2F)cn1

Procedure:
Title compound was prepared using conditions analogous to those described in Example 1 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-(2-bromophenyl)isothiazolidine 1,1-dioxide. MS (ESI): mass calcd. for C19H17FN4O2S, 384.11; m/z found, 385.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.62-8.58 (m, 1H), 8.12 (d, J=1.5, 1H), 7.99 (m, 1H), 7.76-7.71 (m, 1H), 7.49-7.45 (m, 1H), 7.46-7.38 (m, 4H), 4.69 (s, 2H), 3.30-3.04 (m, 4H), 2.39-2.11 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>C(OCC)(=O)C>[C:17]([O:16][C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C@@H:4]([OH:21])[CH2:3][O:2][S:26]([CH3:25])(=[O:28])=[O:27])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)COS(C)(=O)=O
Temperature: 5 °C
Yield: 200.5 %

Procedure:
N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-butyric acid methyl ester 340.4 kg was reduced with sodium borohydride by the same way as described in Reference Example 3, to obtain the crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-butanol, which was dissolved in ethyl acetate 988 kg. To the solution were added methane sulfonylchloride 130.7 kg at 15-0° C. and triethylamine 115.4 kg, successively, and the solution was stirred at 20-30° C. for 15 min. The reaction solution was washed with aqueous 5% sodium bicarbonate solution to separate an organic phase, which was washed with aqueous 10% sodium chloride solution. The separated organic phase was mixed with n-heptane and cooled gradually down to 5° C. or lower to deposit crystals, which were filtered by a Nutsche funnel to obtain a wet crystal of crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-methanesulfonyloxybutane 793 kg (Net.368.9 kg).
Reaction SMILES: [OH:1][CH:2]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].S(O[CH2:30][CH2:31][O:32][CH3:33])(=O)(=O)C.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:1][CH:2]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:30][CH2:31][O:32][CH3:33])=[CH:20][CH:19]=1)[CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(NCCNCC(O)COc1ccc(O)cc1)N1CCOCC1
Reactant: COCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOc1ccc(OCC(O)CNCCNC(=O)N2CCOCC2)cc1

Procedure:
17 g of N-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)-4-morpholinecarboxamide and 6 g of 2-methoxyethyl mesylate and 6.9 g of K2CO3 was refluxed in acetonitril for 20 h. The resulting mixture was filtered and evaporated. The residue was dissolved in methylene chloride and extracted with water containing 1 g of NaOH, then with water and then dried over Na2SO4, filtered and evaporated. The residue was crystallized from ethyl acetate yielding N-(2-((2-hydroxy-3-(4-(2-methoxyethoxy)phenoxy)propyl)amino)ethyl)-4-morpholinecarboxamide. Melting point 69° C. (base).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[C:7]([N+:15]([O-:17])=[O:16])[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:18](=[O:20])[CH3:19])[C:3]1=[C:7]([N+:15]([O-:17])=[O:16])[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN1CCNC1=C(Sc1ccccc1)[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(C)C1=C(Sc1ccccc1)[N+](=O)[O-]

Procedure:
20 ml of acetic anhydride and 1.26 g of 1B were heated together at 100° for 1 hour. The resulting mixture was cooled on an ice-bath and filtered to give 1, as a yellow crystals, m.p.: 191°-193° (with decomposition).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([O:10]COCCOC)[CH:7]=[CH:8][CH:9]=1.Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: CNCc1cccc(OCOCCOC)c1
Reactant: Clc1ccc2ccccc2n1
Product: CN(Cc1cccc(O)c1)c1ccc2ccccc2n1

Procedure:
MS (ESI) 265 (M+H)+. Prepared from 3-[(methylamino)-methyl]-(2-methoxyethoxy-methoxy)benzene (example 28) and 2-chloro-quinoline.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:27]([NH:29][C:30]([N:32]([CH3:34])[NH2:33])=[O:31])[CH3:28].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:15])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:33][N:32]([CH3:34])[C:30]([NH:29][CH2:27][CH3:28])=[O:31])=[O:5]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CCNC(=O)N(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCNC(=O)N(C)NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br

Procedure:
Prophetically, (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid can be reacted with N-ethyl-1-methylhydrazinecarboxamide in the presence of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl) and DMAP to furnish the title molecule (Org. Lett. 2004, 6, 929-931).
Reaction SMILES: [CH2:1]=O.[F:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:8]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:7]=3[C:6]=2[CH:5]=1.N>C(O)=O>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[C:8]3[CH2:20][CH2:21][N:22]([CH3:1])[CH2:23][CH2:24][C:7]=3[C:6]=2[CH:5]=1
Reactant: C=O
Reactant: Fc1ccc(-n2c3c(c4cc(F)ccc42)CCNCC3)cc1
Agent: N
Solvent: O=CO
Product: CN1CCc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)CC1

Procedure:
8.7 ml of a 35% formaldehyde solution are added dropwise to a solution of 9 g of 9-fluoro-6-p-fluorophenyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole in 6.9 g of formic acid. The mixture is heated for 10 minutes to 70°, cooled, poured onto water, made alkaline with concentrated ammonia and extracted with ether. The ether extracts are dried over sodium sulphate and concentrated to give the title compound in hydrochloride form, m.p. 215° (decomp.; from ether/acetone).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:29]([O:32][CH2:33][C:34]1[CH2:41][S:40][CH:39]2[N:36]([C:37](=[O:43])[CH:38]2[NH2:42])[C:35]=1[C:44]([OH:46])=[O:45])(=[O:31])[CH3:30]>C1COCC1>[C:29]([O:32][CH2:33][C:34]1[CH2:41][S:40][CH:39]2[N:36]([C:37](=[O:43])[CH:38]2[NH:42][C:11](=[O:13])[CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[C:35]=1[C:44]([OH:46])=[O:45])(=[O:31])[CH3:30]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc4c(c3)CCO4)C2SC1
Temperature: 0 °C

Procedure:
A solution of 10 mmole of 2,3-dihydo-5-benzofuranyl acetic acid and 10 mmole of triethylamine in 100 ml of THF is cooled to about 0° C. While stirring, isobutylchloroformate (10 mmole) is added and the temperature maintained at 0° C. for 15 minutes. A cold solution of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (10 mmole) and 10 mmole of triethylamine in 80 ml of 50% aqueous THF is added to the previously prepared solution. The mixture is stirred at 5° C. for 1 hour and at room temperature for 1 hour. Then the THF is evaporated and the residue is dissolved in water and washed with ethyl acetate. The aqueous phase is covered with ethyl acetate and the pH is adjusted to 3 with 6N hydrochloric acid. The mixture is filtered and the layers separated. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: Br[C:2]([F:6])=[C:3]([F:5])[F:4].Cl[Si:8]([CH3:19])([CH3:18])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1.C([Li])(CC)C.C1CCCCC1.Cl>CCOCC>[F:6][C:2]([Si:8]([CH3:18])([CH3:19])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=1)=[C:3]([F:5])[F:4]
Reactant: CCOc1ccc([Si](C)(C)Cl)cc1
Reactant: FC(F)=C(F)Br
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCOc1ccc([Si](C)(C)C(F)=C(F)F)cc1
Temperature: -65 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
A -30° C. solution of bromotrifluoroethylene (7.15 g, 0.044 mol) in ether is treated with p-(chlorodimethylsilyl)phenetole (9.54 g, 0.044 mol), cooled to -65° C., treated dropwise with a 1.3M solution of sec-butyllithium in cyclohexane (34.2 mL, 0.044 mol) while maintaining the temperature below -60° C., stirred at -65° C. for 5 hours, stirred at room temperature overnight, cooled to 0° C., treated with dilute hydrochloric acid, and diluted with ether. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue which is distilled to give the title product as a clear liquid (7.66 g, bp 84°-92° C./0.8 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].Cl[CH2:10][CH2:11]Cl>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C
Reactant: ClCCCl
Product: Cc1cccc(CCc2cccc(C)c2C)c1C

Procedure:
o-Xylene and 1,2-dichloroethane were reacted in the presence of anhydrous AlC13 catalyst to obtain 1,2-di(dimethylphenyl)ethane (bromine number: 0.1) of 136 to 148° C. in distillation temperature at 3 to 5 mmHg. This was cracked in the like manner as in Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCCNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
0.39 g (0.001 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane and treated with 1.9 ml (0.01 mol) of N-tert.-butoxycarbonyl-1,4-diaminobutane. The mixture was stirred at 60° C. for 18 hrs., the solvent was removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. There was obtained 0.36 g (77%) of tert-butyl [4-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-ylamino]-butyl]-carbamate as a pale yellow oil. MS (ISP): me/e=501, 499 (C20H26BrN4O4S+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([O:9][CH2:18][CH3:19])=[O:8]
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1cccc(Br)c1

Procedure:
Trans m-bromocinnamic acid (14.8 g), ethanol (173 ml) and concentrated sulfuric acid (0.4 ml) were combined and heated at reflux for 15 hours. About 150 ml of the ethanol was distilled off, and the remaining solution was poured into ice/water (140 ml). The cold mixture was made strongly alkaline with 40% sodium hydroxide and extracted with methylene chloride (4 × 60 ml). The combined methylene chloride extract was dried over anhydrous potassium carbonate. The potassium carbonate was removed by filtration and the solvent stripped off under reduced pressure. Trans ethyl 3-bromocinnamate, was obtained as a partially solidified oil. (IR spectrum was consistent with this compound).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([CH:53]=[CH2:54])[N:44]2[C:43]1=[O:55]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([CH:53]=[CH2:54])[N:44]2[C:43]1=[O:55])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C=C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: C=C[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4OC)C3=O)Cc3ccccc3)C(=O)N12

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,7S,10aS)-5-oxo-7-vinyloctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (36 mg, 0.067 mmol) and Intermediate 73 (23 mg, 0.067 mmol) to give a white solid (30 mg, 59% yield). Anal. Calcd. for C44H54N4O5S m/z 750.7. found: 751.5 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.07 (m, 11H), 7.07-6.89 (m, 3H), 6.36-6.18 (m, 1H), 5.33 (s, 1H), 5.23 (d, J=17.1 Hz, 1H), 5.12 (d, J=10.3 Hz, 1H), 5.06-4.90 (m, 2H), 4.84-4.70 (m, 1H), 4.02-3.84 (m, 1H), 3.79 (s, 3H), 3.47-3.29 (m, 1H), 3.04-2.89 (m, 1H), 2.89-2.75 (m, 2H), 2.75-2.64 (m, 1H), 2.61-2.47 (m, 1H), 2.46-2.23 (m, 8H), 2.10-1.55 (m, 11H), 1.54-1.42 (m, 2H), 1.39-1.15 (m, 2H).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Br:11]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:11][C:7]1[C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[NH:9][CH:8]=1
Reactant: O=c1[nH]cnc2cc[nH]c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cnc2c(Br)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (200 mg, 1.5 mmol, 1 equiv.) and N-bromosuccinimide (320 mg, 1.8 mmol, 1.2 equiv.) in 10 mL of DMF was stirred for 18 hours at room temperature. The reaction was diluted with water and resulting solid was collected by filtration, dried, suspended in MeOH, and filtered. The filtrate was concentrated in vacuo to provide 7-bromo-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one as a beige solid which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([F:11])[C:3]=1[F:12].C([Li])CCC.[CH2:18]([CH:21]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[CH2:22]1)[CH2:19][CH3:20].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2([OH:32])[CH2:28][CH2:27][CH:26]([CH:23]3[CH2:24][CH2:25][CH:21]([CH2:18][CH2:19][CH3:20])[CH2:22]3)[CH2:31][CH2:30]2)=[C:3]([F:12])[C:4]=1[F:11])[CH3:10]
Reactant: CCOc1ccc(Br)c(F)c1F
Reactant: CCCC1CCC(C2CCC(=O)CC2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(O)(c3ccc(OCC)c(F)c3F)CC2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
THF (100 ml) was added to 1-bromo-4-ethoxy-2,3-difluorobenzene (5.1 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to −78° C. n-Butyllithium (1.57 M, in a hexane solution) (13.8 ml) was added dropwise at a temperature of −70° C. or lower. The stirring was continued at −78° C. for another 2 hours, and 4-(3-propylcyclopentyl)-cyclohexanone (3.0 g) in a THF (10 ml) solution was added dropwise at a temperature of −70° C. or lower. After the mixture had been stirred at −78° C. for another 1 hour, it was warmed to room temperature, and a saturated aqueous solution of ammonium chloride (50 ml) was added. The mixture was separated, and the water layer was extracted with ethyl acetate three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/9 by volume) to give 1-(4-ethoxy-2,3-difluorophenyl)-4-(3-propylcyclopentyl)cyclohexanol (5.0 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(O[CH2:9][C:10]1[CH2:17][S:16][CH:15]2[N:12]([C:13](=[O:28])[CH:14]2[NH:18][C:19](=[O:27])[CH2:20][C:21]2[S:22][C:23](=[O:26])[S:24][CH:25]=2)[C:11]=1[C:29]([OH:31])=[O:30])(=O)C>O.C(=O)(O)[O-].[Na+]>[N:1]([CH2:9][C:10]1[CH2:17][S:16][CH:15]2[N:12]([C:13](=[O:28])[CH:14]2[NH:18][C:19](=[O:27])[CH2:20][C:21]2[S:22][C:23](=[O:26])[S:24][CH:25]=2)[C:11]=1[C:29]([OH:31])=[O:30])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Temperature: 50 °C
Yield: 44.8 %

Procedure:
Sodium azide (0.871 g.) is added to a solution of 3-acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3 g.) in water (60 cc.) and sodium bicarbonate (0.588 g.), and the mixture is heated to 50° C. for 16 hours. It is allowed to cool and sodium bicarbonate (0.4 g.) is added. The mixture is extracted twice with ethyl acetate (40 cc.). The aqueous phase is treated with decolourising charcoal and brought to pH 2 by adding 6 N hydrochloric acid. A product precipitates, and is extracted with ethyl acetate (240 cc.). The organic extracts are dried over sodium sulphate and then concentrated to dryness under reduced pressure (20 mm.Hg). A residue (1.9 g.) is obtained, which is recrystallised from acetonitrile (18 cc.) to give 3-azidomethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (1.29 g.), m.p. 160° C., after a further recrystallisation from acetonitrile.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][C:7]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[O:17]=[C:7]1[NH:8][C:9](=[O:16])[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[N:6]1[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[S:25]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CNCCCn1c2c(c(=O)[nH]c1=O)CCCC2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(CCCn1c2c(c(=O)[nH]c1=O)CCCC2)S(=O)(=O)c1ccc(F)cc1
Yield: 34.1 %

Procedure:
A solution of 75 mg (0.32 mmol) of 1-[3-(methylamino)propyl]-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione and 61.5 mg (0.32 mmol) of 4-fluorophenylsulphonyl chloride in 3 ml of pyridine is stirred at room temperature overnight. The reaction mixture is then adjusted to pH 1 using 2-molar hydrochloric acid and extracted twice with in each case 20 ml of ethyl acetate. The organic phase is concentrated under reduced pressure and the resulting residue is purified by preparative HPLC (RP-C18, acetonitrile/water gradient). This gives 43.1 mg (34% yield) of the product as an amorphous solid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[BrH:15].O>C1(C)C=CC=CC=1>[Br:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCCCCCCCCCCO
Reactant: Br
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCCCCCCCCCCBr

Procedure:
To a stirred solution of dodecane-1,12-diol (8.365 g, 42.75 mmol), 48% HBr in water (9.7 ml, 85.50 mmol) and toluene (120 ml) were added and the reaction mixture refluxed for 3 h. The reaction mixture was then concentrated, the crude compound was dissolved in DCM (150 ml), washed with water, NaHCO3 brine solution, dried over MgSO4 and concentrated. The crude product was purified by silica gel column (5% EtOAc in hexane) to obtain 12-bromododecan-1-ol as an off-white low melting solid (8.87 g, 78%).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S-2:19].[Na+].[Na+].O>CN(C)C=O>[SH:19][C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S
Temperature: 25 °C
Yield: 97.6 %

Procedure:
5.0 g (18.4 mmol) of 2-chloro-4-(3-trifluoromethylpyrazolyl)benzonitrile in N,N-dimethylformamide was stirred together with 1.86 g (23.9 mmol) of sodium sulfide at 120° C. for 30 minutes. The reaction mixture was cooled to room temperature, mixed with 100 ml of water, washed with 30 ml of ethyl acetate, and the aqueous layer was adjusted at pH 5-6 with citric acid, and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 50 ml of water twice and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure to obtain 2-mercapto-4-(3-trifluoromethylpyrazolyl)benzonitrile (yield 97.6%) as a pale yellow powder, which was used in Example 1 (2) as the starting material.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[C:9]1([C:15]2[CH2:16][CH:17]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:18](=[O:21])[NH:19][N:20]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1NN=C(c2ccccc2)CC1c1ccccc1
Reaction time: 8 h
Yield: 50 %

Procedure:
135 ml (135 mmole) of a solution of phenylmagnesium bromide (1M) in THF was added to a hot suspension of 6-phenylpyridazinone compound 7.8 g (45 mmole) in dry toluene (50 ml). The mixture was refluxed for 8 h, left overnight at ambient temperature, then decomposed with a saturated solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with 100 ml of ethyl acetate. The solvent was removed and the residue was crystallized from ethanol. The crystals were collected by filtering and dried over a medium frit sintered glass funnel in vacuo to give 5.6 g of white crystals. Yield was 50%, confirmed by ESI-MS. ESI-MS: m/z 250.1 (M+H+).