Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+].ClC1C(C2C=C3C(=CC=2)NN=C3)=CC=CN=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[Cl:12][C:13]1[C:18]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[CH3:11])=[CH:4][CH:3]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Cn1ncc2ccc(Br)cc21
Reactant: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Clc1ncccc1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1ncc2ccc(-c3cccnc3Cl)cc21
Yield: 78.6 %

Procedure:
Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,6-(-2-chloropyridin-3-yl)-1-methyl-1H-indazole was prepared by heating the mixture of 6-bromo-1-methyl-1H-indazole (2.0 g, 9.5 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (2.2 g, 9.4 mmol), Pd(PPh3)4 (0.54 g, 0.46 mmol) and 2M aq. Na2CO3 (14 mL, 28 mmol) in 1,4-dioxane (75 mL) under argon atmosphere for 12 h. Upon extractive work-up as discussed in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole with CH2Cl2 and purification of the concentrate by flash silica gel column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g, 30-50% EtOAC/hexanes eluting solvent gradient upon dry loading the concentrate absorbed on silica gel) provided 6-(-2-chloropyridin-3-yl)-1-methyl-1H-indazole as a white solid (1.8 g, 77%). 1H NMR (DMSO-d6): δ 8.45 (dd, 1H, J=1.7 and 4.7 Hz), 8.09 (s, 1H), 7.94 (dd, 1H, J=2.0 and 7.6 Hz), 7.82 (d, 1H, J=8.5 Hz), 7.74 (s, 1H), 7.54 (dd, 1H, J=4.7 and 7.6 Hz),7.22 (d, 1H, J=8.5 Hz), 4.06 (s, 3H).LCMS: rt 6.80 min (A), purity 97%, MS (m/e) 244 (MH+)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:47]=[C:46]([S:48]([N:51](CC2C=CC(OC)=CC=2OC)[C:52]2[S:53][CH:54]=[N:55][N:56]=2)(=[O:50])=[O:49])[C:45]([F:68])=[CH:44][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:14][C:13]=1[C:28]1[N:32]([CH:33]2[CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]2)[N:31]=[CH:30][CH:29]=1>ClCCl>[NH:35]1[CH2:34][CH:33]([N:32]2[C:28]([C:13]3[CH:14]=[C:15]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[CH:16]=[CH:17][C:12]=3[O:11][C:10]3[C:9]([Cl:8])=[CH:47][C:46]([S:48]([NH:51][C:52]4[S:53][CH:54]=[N:55][N:56]=4)(=[O:50])=[O:49])=[C:45]([F:68])[CH:44]=3)=[CH:29][CH:30]=[N:31]2)[CH2:36]1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnn2C2CNC2)cc1F
Temperature: 40 °C
Yield: 127.3 %

Procedure:
Trifluoroacetic acid (0.50 mL, 6.53 mmol) was added to a solution of tert-butyl 3-{5-[4-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,3,4-thiadiazol-2-yl)amino]sulfonyl}-5-fluorophenoxy)-4′-(trifluoromethyl)biphenyl-3-yl]-1H-pyrazol-1-yl}azetidine-1-carboxylate (Preparation 40, 419 mg, 0.465 mmol) in dichloromethane (20 mL). The mixture was then heated to 40° C. for 18 hours under an atmosphere of nitrogen. The reaction was then cooled to room temperature and concentrated in vacuo to afford a brown residue (385.4 mg). The residue was purified by preparative HPLC (Trilution method) to afford the title compound as a white solid (46.3 mg, 11% over 2 steps).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([Cl:21])[N:6]2S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].Cl>CC(O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([Cl:21])[NH:6]2
Reactant: Cc1ccc(S(=O)(=O)n2c(Cl)cc3c(Br)cccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Clc1cc2c(Br)cccc2[nH]1
Temperature: 120 °C

Procedure:
4-Bromo-2-chloro-1-[(4-methylphenyl)sulfonyl]-1H-indole (215 mg), IPA (2.5 ml) and 2 M NaOH (aq) (2.5 ml) were mixed in a microwave vial and heated in the microwave for 30 min at 120° C. The reaction was acidified using 2M HCl (aq) and then extracted with DCM, which was passed through a hydrophobic frit, then evaporated to dryness. The residue was triturated with methanol which was then evaporated to afford the title compound, 112 mg.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][OH:11].[N+:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1
Reactant: Cn1c([N+](=O)[O-])cnc1CO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Cn1c([N+](=O)[O-])cnc1COc1ccc([N+](=O)[O-])cc1

Procedure:
m.p. 150° C, from 15.7 g (0.1 mole) of 1-methyl-2-hydroxymethyl-5-nitro-imidazole (MHNI) and 14.1 g (0.1 mole) of 4-nitrofluorobenzene.
Reaction SMILES: CC(C)(C)C(OC[N:7]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[N:8]1)=O.[OH-].[Na+].CC(O)=O>C1COCC1.CO>[NH:7]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[N:8]1
Reactant: CC(C)(C)C(=O)OCn1ccc(-c2cccc(-c3ccc(C=O)cc3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cccc(-c3cc[nH]n3)c2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of [3-(4′-formyl-3-biphenylyl)-1H-pyrazol-1-yl]methyl 2,2-dimethyl-propanoate (0.162 g; 0.45 mmol) in 1:1 THF/MeOH (5 mL total vol) at room temperature was added NaOH (1.1 mL of a 1.0M solution; 1.1 mmol). After 30 min, HOAc (0.08 mL; 1.4 mmol) was added and the mixture was concentrated in vacuo. The residue was partitioned between EtOAc/water, layers were separated, the organic layer was washed (satd NaHCO3, brine), dried over Na2SO4 and concentrated in vacuo. The residue was redissolved in EtOAc, washed (1M HCl, water, brine), dried over Na2SO4 and concentrated in vacuo, affording the title compound as a glassy semi-solid which was used without further purification. LC/MS (method A) 2.42 min; m/z 249 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]#[N:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:67]=[N+:68]=[N-:69])(C)C.[SiH3]N=[N+]=[N-]>C(#N)C.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]1[N:12]([CH2:13][CH2:14][C:15]#[N:16])[N:69]=[N:68][N:67]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC#N
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [N-]=[N+]=N[SiH3]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)c1nnnn1CCC#N
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2-t-butoxycarbonylamino-3-biphenyl-4-yl-N-(2-cyanoethyl)-propionamide (20 g, 51.2 mmol) in acetonitrile (220 mL) under nitrogen is added triphenyl phosphine (33.6 g, 128 mmol). The suspension is cooled to 0°. Diisopropyl azodicarboxylate (24.8 mL, 125.6 mmol) is placed in an addition funnel. In a separate addition funnel is placed trimethylsilyl azide (16.8 mL, 127.2 mmol). The two reagents are introduced dropwise, allowing the azoester to be added about 1 minute faster than the silyl azide and keeping the reaction temperature below 10°. The slightly yellow suspension is gradually (10°/hour) warmed up to 35°. The reaction is then monitored by TLC (ethyl acetate/hexane:3/1) until practically complete conversion is observed. A clear solution is then usually obtained. The excess of azide is destroyed by cooling the solution to 10° and adding sodium nitrite (3.2 g) in water (16 mL), followed by acetic acid (16 mL). The mixture is stirred at 20°-25° for at least 2 hours, until a nitrite-free aliquot of the acetonitrile layer shows a negative zide test (ferric chloride paper). The lower salt phase is separated and the organic layer is concentrated in vacuo at 45°. The semi-solid residue is dissolved in isopropanol at 80°. Some insoluble material is filtered from the hot solution. The title compound crystallizes at about 60° after seeding. The suspension is cooled to 25° within 2 hours then left at 0°-5° for 1 hour. The product is filtered, washed with cold ispropanol (3×20 mL) and dried under reduced pressure at 50° to constant weight to obtain (S)-3-[5-(1-t-butoxycarbonylamino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[CH2:16][OH:17])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:8]([CH2:16][OH:17])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(CO)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)c(CO)c1
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a solution of (2-morpholin-4-yl-5-nitro-phenyl)-methanol (870 mg) in ethanol (40 mL), palladium hydroxide (87 mg) is added and the mixture is stirred in a Parr-apparatus under hydrogen pressure (10 bars) for 4 hours. The reaction mixture is filtrated over Celite 521, washed with ethanol and concentrated in vacuo to give the title compound (640 mg, 83%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(O[CH2:18][CH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)(C)(=O)=O>CN(C=O)C>[C:1]1(=[O:11])[N:5]([CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCCCc1ccc(C#N)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To 100 ml of DMF suspension of 21.1 g (0.114 mol) of potassium phthalimide was added 50 ml of DMF solution of 13.6 g (57 mmols) of crude 4-(3-mesyloxypropyl)benzonitrile. The reaction mixture was stirred at 90° C. for 3 hours, then cooled to room temperature and poured into 200 ml of ice-water, followed by extraction with ether-benzene (1:1). The organic layer was dried over Na2SO4 and concentrated, giving 14.0 g (yield 85%) of 4-(3-phthalimidopropyl)benzonitrile.
Reaction SMILES: [CH:1]1([C:6]2[CH:32]=[CH:31][C:9]([CH2:10][O:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]3[CH2:21][CH2:22][CH2:23][CH:24]([CH2:25][C:26]([O:28]CC)=[O:27])[C:16]3=[CH:15]4)=[CH:8][C:7]=2[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>O1CCOCC1>[CH:1]1([C:6]2[CH:32]=[CH:31][C:9]([CH2:10][O:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]3[CH2:21][CH2:22][CH2:23][CH:24]([CH2:25][C:26]([OH:28])=[O:27])[C:16]3=[CH:15]4)=[CH:8][C:7]=2[C:33]([F:36])([F:34])[F:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC1CCCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 45 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a solution of ethyl 2-(2-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (143 mg, 0.286 mmol) in dioxane (1.5 mL) was added 1 M LiOH aqueous solution (1.15 mL, 1.145 mmol). The reaction mixture was stirred at 45° C. for 3 h. A portion of the solvent was removed in vacuo. The remaining mixture was diluted with water, acidified with 0.5 M aqueous citric acid to pH 4, and extracted with ethyl acetate. The combined organics were washed with water, dried over anhydrous Na2SO4, and concentrated to give the title compound (105 mg). LCMS m/z=472.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.54-1.66 (m, 3H), 1.67-1.80 (m, 2H), 1.80-1.92 (m, 2H), 2.00-2.24 (m, 5H), 2.64 (dd, J=16.1 and 8.7 Hz, 1H), 3.01 (dd, J=16.1 and 5.3 Hz, 1H), 3.33-3.42 (m, 1H), 3.45-3.55 (m, 1H), 3.85-3.94 (m, 1H), 4.12-4.18 (m, 1H), 5.08 (s, 2H), 6.22 (s, 1H), 6.90 (dd, J=8.8 and 2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.70 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:15][CH:16]=O>C1COCC1>[CH3:16][NH:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[Cl:7]
Reactant: O=CNc1cccc(F)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 98.3 %

Procedure:
To a stirred suspension of 95% lithium aluminum hydride (2.19 g, 58 mmol) in anhydrous THF (10 mL) at 0° C., was added dropwise a solution of N-(2-chloro-3-fluoro phenyl)-formamide (2.3 g, 13.2 mmol) in anhydrous THF (20 mL). The reaction mixture was allowed to slowly warm to room temperature and was stirred for a further 40 mins. The mixture was cooled to 0° C. and was quenched via the sequential addition of water (4 mL), 15% aq. NaOH (2 mL), then water (4 mL). Organics were extracted into a mixture of 3:1 DCM:IPA (100 mL) and washed with water (50 mL). The organic layer was separated and dried over MgSO4. Filtration then concentration in vacuo gave N-methyl-2-chloro-3-fluoroaniline 29-1 (2.07 g, 99%) as a yellow oil. MS (M+H)+: 160.1, tR=2.21 min (method 1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:24][CH3:25])(=[O:23])[CH:20]([CH3:22])[CH3:21].CN(P(N(C)C)(N(C)C)=O)C.[CH2:37]([O:40][CH2:41]Cl)[CH2:38][CH3:39].[Cl-].[NH4+]>C1COCC1>[CH3:39][CH2:38][CH2:37][O:40][CH2:41][C:20]([C:19]([O:24][CH3:25])=[O:23])([CH3:22])[CH3:21]
Reactant: CCCOCCl
Reactant: COC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOCC(C)(C)C(=O)OC
Temperature: -78 °C
Yield: 73.9 %

Procedure:
To a solution of anhydrous diisopropylamine (11.9 g, 0.118 mol) in 100 ml of anhydrous THF was added dropwise under argon atmosphere a solution of n-butyl lithium in hexane (1.59N, 74.2 ml, 0.118 mol) with stirring at -78° C. and further stirred for 30 min. To this solution was addded dropwise a solution of methyl isobutyrate (10.0 g, 0.098 mol) in anhydrous THF (10 ml). The resulting mixture was stirred for 30 min. HMPA (7 g, 0.039 mol) and chloromethyl propyl ether (13.8 g, 0.127 mol) were added, and stirred for 30 min. The reaction mixture was allowed to warm to room temperature. To the mixture was then added an aqueous saturated solution of ammonium chloride (300 ml) cooled in an ice bath. The organic layer was washed with 30 ml of water and with 20 ml of brine, and dried over anhydrous sodium sulfate. The solvent was distilled out successively at normal pressure and then the residue was distilled in vacuo to give a colourless and transparent oil of methyl 2,2-dimethyl-4-oxaheptylate (12.6 g, 0.0724 mol, b.p. 84°-87° C./30 mmHg, yield: 73.9%). The product was assigned the structure by the following data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:3][CH:4]=1
Reactant: c1cn[nH]c1
Reactant: Clc1ccc(Br)cc1
Product: Clc1ccc(-n2cccn2)cc1

Procedure:
1-(4-Chlorophenyl)-1H-pyrazole was prepared from 1-bromo-4-chlorobenzene and pyrazole according to the procedure of Cristau et al., Eur. J. Org. Chem. 2004, 4, 695-709.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH:8]([CH2:10][CH3:11])[CH3:9])=[CH:4][CH:3]=1.[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]([CH2:10][CH3:11])[CH3:9])[C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[S:22])=[CH:12][CH:13]=1
Reactant: S=C=Nc1ccccc1
Reactant: CCC(C)NCc1ccc(Cl)cc1
Solvent: CCOCC
Product: CCC(C)N(Cc1ccc(Cl)cc1)C(=S)Nc1ccccc1
Yield: 89.1 %

Procedure:
20 g of N-(4-chlorobenzyl)-N-sec.-butylamine were dissolved in 500 ml of ether. To the resulting solution, a solution of 14 g of phenyl isothiocyanate in 50 ml of ether was added dropwise, under cooling and stirring. After the dropwise addition, the temperature of the solution was gradually raised, and the solution was then stirred at room temperature for about 10 hours. The crystals which had been formed were separated by filtration. After recrystallization with a solvent mixture of hexane and ethyl alcohol, 30 g of N-(4-chlorobenzyl)-N-sec.-butyl-N'-phenylthiourea were obtained. Yield: 91%. Melting point: 134°-134.5° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[N+:4]([O-:29])[CH:3]=1.[ClH:30]>C(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[CH:11]=[C:2]([F:1])[CH:3]=[N+:4]([O-:29])[C:5]=3[CH:6]=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c2cc(F)c[n+]3[O-])CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CCN(CCn2c(=O)ccc3c2cc(F)c[n+]3[O-])CC1
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl {1-[2-(7-fluoro-5-oxido-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-4-piperidinyl}carbamate (335 mg, 0.824 mmol) was dissolved in DCM (3 mL) and 4M HCl in 1,4-dioxane (0.830 mL (ca. 4 eq.) was added. A further 10 mL DCM was added to disperse the solid, then a further 0.830 mL 4M HCl in 1,4-dioxane was added. The mixture was left at room temperature for 30 minutes, then the solvents were removed under reduced pressure to give title compound as a white solid (315 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1)(=O)=O.FC(F)(F)C(O)=O.[CH3:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([N:33]2[CH2:38][C:37]3([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[O:36][CH2:35][CH2:34]2)=[O:32])[N:30]=1.C(N(CC)CC)C>C(#N)C>[CH3:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([N:33]2[CH2:38][C:37]3([CH2:43][CH2:42][N:41]([CH2:6][CH2:7][CH2:8][O:9][C:10]4[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=4)[CH:16]=[O:17])[CH2:40][CH2:39]3)[O:36][CH2:35][CH2:34]2)=[O:32])[N:30]=1
Reactant: CS(=O)(=O)OCCCOc1cccc(C=O)c1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCOc4cccc(C=O)c4)CC3)C2)cs1

Procedure:
A solution of 3-(3-formylphenoxy)propyl methanesulfonate (example 95, step a) (0.209 g) and (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.32 g) and triethylamine (0.282 mL) in acetonitrile (10 mL) were heated at 65° C. for 18 hours. The solvent was evaporated off under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2% methanol and 1% triethylamine in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.157 g.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]2[NH:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1N
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)c2nc3ccccc3[nH]2)cc1
Temperature: 100 °C

Procedure:
A mixture of diphenylacetaldehyde (2-1, 1.64 mL, 9.25 mmol, 1 equiv), 1,2-diaminobenzene (0.787 mL, 9.25 mmol, 1.00 equiv) and sodium metabisulfite (2.11 g, 11.1 mmol, 1.20 equiv) in DMF (10 mL) was heated at 100° C. for 18 h. The reaction mixture was cooled to 23° C. and filtered. The filtrate was suspended with sonication in a 1:1 mixture of saturated aqueous sodium chloride solution and saturated aqueous sodium carbonate solution then extracted with ethyl acetate (6×150 mL). The combined organic layers were dried voer sodium sulfate and concentrated. The residue was suspended in ethyl ether (50 mL), filtered, washed with ethyl ether (2×50 mL) and air dried to give 2-(diphenylmethyl)-1H-benzimidazole (2-2) as a white solid. 1H NMR (300 MHz, DMSO) δ 12.3 (br s, 1H), 7.50 (m, 2H), 7.34 (m, 8H), 7.24 (m, 2H), 7.08 (m, 2H), 5.74 (s, 1H). LRMS m/z (M+H) 235.0 found, 335.1 required.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH2+:4].CC([O-])(C)C.[K+].C([O:14][C:15](=O)[CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=2)[C:19](=[O:30])[N:18]1[CH2:31][C:32]([F:35])([F:34])[F:33])C.Cl>O>[O:30]=[C:19]1[C:20]2[C:25](=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)[CH:17]([CH2:16][C:15]([NH:4][C:3]([NH2:5])=[NH:2])=[O:14])[N:18]1[CH2:31][C:32]([F:34])([F:33])[F:35]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: N=C(N)NC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
1.24 g guanidinium hydrochloride and 1.21 g of KOtBu were suspended using 30 ml of DMF(anhydrous) and stirred for 30 minutes at ambient temperature. Then, a solution of 0.8 g of [3-oxo-2-(2,2,2-trifluoro-ethyl)-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl]-acetic acid ethyl ester in 5 ml of DMF(anhydrous) were added and the mixture was stirred for 17 h at ambient temperature. The mixture was then poured into 100 ml of water and the pH was adjusted to pH=8 using aqueous HCl-solution. The aqueous layer was extracted three times using 100 ml of EA each. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. Chromatography on silica gel using EA/MeOH 3:1 yielded 0.56 g of an amorphous solid (Rf(EA/MeOH 3:1)=0.45, MS (ES+): 383 (M+1)+).
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24])([CH3:17])([CH3:16])[CH3:15].C([Li])(CC)C.[Br:30]C(F)(F)C(F)(F)Br>C1CCCCC1.O1CCCC1>[Br:30][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:19]=1[SH:24]
Reactant: CC(C)(C)c1ccccc1S
Reactant: FC(F)(Br)C(F)(F)Br
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(Br)c1S
Temperature: 0 °C
Reaction time: 14 h

Procedure:
To a solution of freshly distilled tetramethylethylenediamine (7.5 mL, 50 mmol) in dry cyclohexane (35 mL) is added dropwise at 24° C. a solution of n-butyl lithium in hexanes (31 mL, 50 mmol). After addition is complete, the reaction mixture is cooled to 0° C. A solution of 2-tert-butylthiophenol (3.77 g, 22.7 mmol) in dry cyclohexane (10 mL) is added at a rate such that the reaction temperature stays below 10° C. The reaction is allowed to stir at 24° C. for 14 h. A solution of sec-butyl lithium in hexanes (17.5 mL, 22.7 mmol) is added at this temperature, and the color of the reaction changes from yellow to orange. After 1 h, the reaction mixture is added at -78° C. to a solution of 1,2-dibromotetrafluoroethane (5.4 mL, 45.4 mmol) in dry tetrahydrofuran (100 mL). The mixture is allowed to warm to 24° C., and is partitioned against 0.1N HCl (100 mL). The organic phase is dried (MgSO4), filtered and evaporated to give 2-bromo-6-tert-butylthiophenol as a yellow oil.