Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=3[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][CH2:25][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:34]([NH:37][CH2:38][CH:39]=[CH2:40])[CH:35]=[CH2:36]>C(O)(=O)C>[Cl:21][C:20]1[C:15]2[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][CH2:25][C@H:12]3[C:11]3[N:10]([CH:9]=[N:8][C:7]=3[C:5]3[O:6][C:2]([CH2:3][N:37]([CH2:38][CH:39]=[CH2:40])[CH2:34][CH:35]=[CH2:36])=[CH:1][N:4]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: C=CCNCC=C
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: C=CCN(CC=C)Cc1cnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)o1
Temperature: 25 °C
Reaction time: 19 h
Yield: 28.7 %

Procedure:
A solution of 7.95 g (0.0224 mol) of (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 7.56 g (0.0336 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 19 hrs. and at 50° for 4 hrs. the dark brown suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The red-brown solid residue was dissolved in 100 ml of THF, treated with 23.9 ml (0.194 mol) of diallylamine and stirred at room temperature for 48 hrs. The solution obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the dark brown product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There were obtained 2.89 g (29%) of (S)-8-chloro-1-(5-diallylaminomethyl-oxazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one as a yellow foam; [α]D20 =+11.3° (MeOH, c=1%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[CH:21]([N:24]([CH:27]([CH3:29])C)CC)([CH3:23])C.N1CCCC1>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:24]1[CH2:21][CH2:23][CH2:29][CH2:27]1)=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCCC3)nc2c1C#N
Yield: 96.8 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.13 g, 0.45 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (92.0 μl, 0.54 mmol) and pyrrolidine (41.0 μl, 0.50 mmol) were added. This was heated under reflux for 4 hours, and diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=100:1) to obtain a pale yellow oil (0.14 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.N12CCCN=C1CCCC[CH2:12]2>ClCCl.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:12])=[C:4]([F:10])[CH:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: ClCCl
Product: C=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.0 g (49.3 mmol) of 4-bromo-2-fluorobenzaldehyde were dissolved in 40 ml of dichloromethane, admixed with 9.6 ml (9.7 g, 64.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 19.4 g (54.2 mmol) of methyltriphenylphosphonium bromide and stirred at RT for 3 h. The reaction mixture was purified on silica gel (eluent: dichloromethane). The product fractions were combined, concentrated under reduced pressure and dried under high vacuum. Yield: 4.5 g (41% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29](O)=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:35])=O>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([Cl:35])=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)O)s5)nn34)ccnc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)Cl)s5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carboxylic acid (prepared by General Method A) (0.150 g, 0.335 mmol) in dichloromethane (2 mL) was added thionyl chloride (0.734 ml, 10.1 mmol and DMF (1 drop). The solution was stirred at room temp for three hours then concentrated and taken forward without further purification.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[F:5][C:6]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.BrBr.N>C(O)(=O)C.O>[F:5][C:6]([F:20])([C:16]([F:17])([F:18])[F:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]=[C:2]([NH2:3])[S:1][C:14]=2[CH:15]=1
Reactant: Nc1ccc(OCC(F)(F)C(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc(OCC(F)(F)C(F)(F)F)cc2s1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
Potassium thiocyanate (4.27 g) is added to a solution of 4-(2,2,3,3,3-pentafluoropropoxy)aniline (2.65 g) in acetic acid (25 cc), and the mixture is stirred for 10 minutes at a temperature in the region of 20° C. To the solution thereby obtained, a solution of bromine (0.56 cc) in acetic acid (5 cc) is introduced dropwise in the course of 35 minutes at a temperature of between 22° C. and 35° C., and the mixture is then stirred for 16 hours at a temperature in the region of 20° C. The reaction mixture is poured into a mixture of water and ice (150 cc), alkalinized with 28% strength ammonia solution (35 cc) and extracted 3 times with ethyl acetate (170 cc in total). After settling has taken place, the organic solution is separated and washed with distilled water to pH 8, dried over magnesium sulphate, filtered and evaporated at 50° C. under reduced pressure (20 mm Hg; 2.7 kPa). The product obtained (3.2 g) is purified by chromatography on a column of silica (250 g; particle size: 0.063-0.200 mm) with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluant, and recrystallized in toluene (15 cc). 6-(2,2,3,3,3-Pentafluoropropoxy)-2-benzothiazolamine (1.27 g), m.p. 147° C., is obtained.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[OH:20])[N:10]=[CH:9][N:8]=1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C(N(CC)CC)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[O:20][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:10]=[CH:9][N:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: O[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)O[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Temperature: 0 °C

Procedure:
To 3.2 ml of tetrahydrofuran were added 0.37 g of 4-chloro-6-(cis-2-hydroxycyclohexyloxy)pyrimidine and 0.45 ml of triethylamine, to which 0.25 ml of chlorotrimethylsilane was slowly added dropwise with stirring at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.5 g of 4-chloro-6-(cis-2-trimethylsilanyloxycyclohexyloxy)pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=O)[CH:5]=[CH:4][C:3]1=2.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(OCC)(=O)C.CCCCCC>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:1])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Reactant: Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(F)cc3)ccc21
Yield: 60.7 %

Procedure:
In a manner analogous to Example 1, 2 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxylic acid and 1 g of 4-fluoroaniline were used to obtain 1.7 g of 4'-fluoro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxanilide in colorless crystals, m.p. 163°-165° C. (from ethyl acetate/hexane).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([OH:30])=O)[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.C1COCC1.[CH3:36][NH:37][CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([N:37]([CH3:38])[CH3:36])=[O:30])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=C(O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a stirred mixture of 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (65 mg, 0.153 mmol) from Example 81 and TEA (77 mg, 0.767 mmol) in a mixture of anhydrous THF (1.5 mL) and anhydrous DMF (0.5 mL) at rt was added dimethylamine (2 M solution in MeOH, 383 μL, 0.767 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.230 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxamide (33 mg, 48%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.96 (d, J=7.54 Hz, 1H), 7.68 (s, 1H), 7.20-7.33 (m, 2H), 5.50 (s, 2H), 4.73 (d, J=4.90 Hz, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.99 (br. s., 6H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH:23]=O)[CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:26]1([C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH3-]C#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][N:35]2[CH2:36][CH2:37][C:32]([OH:38])([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:33][CH2:34]2)[CH2:10][C:11]([N:13]2[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[CH:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=CCC(CC(=O)n1ccc2ccccc21)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
1-[3-(3,4-dichlorophenyl)-1,5-dioxopentyl]-1H-indole (740 mg), in MeOH/THF (1:1, 30 mL) was treated sequentially with molecular sieves 3A (880 mg), 4-phenyl-4-hydroxypiperidine HCl (880 mg) and NaBH3CN (130 mg). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was with quenched with water (20 mL) and diluted with CH2Cl2 (50 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×50 mL) The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude oil. Silica gel chromatography eluting with 1-2% MeOH/CH2Cl2 gave the title compound (600 mg). Mass spectrum (CI): 521.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH2:11](Br)[CH3:12]>>[CH2:11]([O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH3:12]
Reactant: CCBr
Reactant: CC(C)C(O)C(C)(C)CO
Product: CCOCC(C)(C)C(O)C(C)C
Yield: 90 %

Procedure:
Treatment of 2,2,4-trimethylpentan-1,3-diol with ethyl bromide employing the alkylation reaction conditions described above provided 1-ethoxy-2,2,4-trimethylpentan-3-ol in 90.0% yield (313.2 g, b.p.=79–80 C./3.2 mmHg).
Reaction SMILES: CS(O[CH2:6][C:7]([O:19][CH3:20])([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])[CH2:8][CH2:9][CH3:10])(=O)=O.[Na].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1>CS(C)=O>[N:22]1([CH2:6][C:7]([O:19][CH3:20])([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH2:8][CH2:9][CH3:10])[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: CCCC(COS(C)(=O)=O)(OC)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CS(C)=O
Product: CCCC(Cn1cncn1)(OC)c1ccc(Cl)cc1Cl
Temperature: 120 °C
Reaction time: 16 h

Procedure:
The crude product prepared in (a) is dissolved in 50 ml of absolute dimethyl sulfoxide, and 2.2 g (24 mmoles) of the sodium salt of 1,2,4-triazole are added. The reaction mixture is stirred for 16 hours at a bath temperature of 120° C. The resulting dark solution is cooled to room temperature, poured into ice water and extracted twice with ethyl acetate. The combined extracts are washed four times with half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified by colum chromatography (silica gel; 1:1 ethyl acetate/petroleum ether) and affords 3.2 g (=64% of theory) of a colourless oil. Boiling point 170°-175° C./0.04 mbar. 60 MHz-1H-NMR (CDCl3): δ=7.75 and 7.60 ppm (2s, 2H of the triazole); 6.9-7.5 ppm (m, 3H, aromatic); 4.8 ppm (4 lines AB spectrum, 2H, CH2N); 3.4 ppm (s, 3H, OCH3); 1.7-2.5 ##STR35## 0.7-1.5 ppm (m, 5H, CH2CH3).
Reaction SMILES: [CH:1](OCC)=[O:2].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C@@H:13]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:15]([CH2:16][CH2:17][C@@H:18]3[C@@H:29]2[C:28](=[O:34])[CH2:27][C@@:26]2([CH3:35])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C:23](=[O:25])[CH3:24])[CH2:14]1.[H-].[Na+].CO>CS(C)=O>[CH:1]([CH2:24][C:23](=[O:25])[C@@H:22]1[C@:26]2([CH3:35])[C@H:19]([C@H:18]3[C@H:29]([C:28](=[O:34])[CH2:27]2)[C@:30]2([CH3:33])[C@H:15]([CH2:14][C@H:13]([O:12][CH:7]4[CH2:8][CH2:9][CH2:10][CH2:11][O:6]4)[CH2:32][CH2:31]2)[CH2:16][CH2:17]3)[CH2:20][CH2:21]1)=[O:2]
Reactant: CCOC=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: C[C@]12CC[C@@H](OC3CCCCO3)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CC=O)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 4 h

Procedure:
Ethyl formate (0.7 ml) was added to a mixture of 3α-(tetrahydropyran-2ξ-yloxy)-5α-pregnane-11,20-dione (840 mg) and sodium hydride (130 mg) in dry dimethyl sulphoxide (15 ml). The mixture was stirred, under nitrogen for 11/4 hrs., then treated with methyl alcohol to destroy excess sodium hydride, and poured into dilute hydrochloric acid. The precipitate was collected, washed and dried to give title compound (943 mg).
Reaction SMILES: [S].Cl[C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[N+:13]([O-])=O.[C:16](=[S:18])=[S:17].COS(OC)(=O)=O>O>[C:8]([NH:7][C:6]1[CH:11]=[CH:12][C:3]2[S:17][C:16]([SH:18])=[N:13][C:4]=2[CH:5]=1)(=[O:10])[CH3:9]
Reactant: S=C=S
Reactant: CC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [S]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CC(=O)Nc1ccc2sc(S)nc2c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
A mixture of Na2S.9H2O (65 g, 0.28 mol), sulfur (25 g, 0.78 mol) and water (150 mL) were heated with stirring at 90° C. for 10 min, and then poured into a flask charged with the above 4′-chloro-3′-nitroacetanilide (21.5 g, 0.10 mol). The resulting mixture was heated at 80° C. for 10 min, and then CS2 (12 mL, 0.2 mol) was added dropwise while maintaining a gentle reflux. The resulting mixture was heated at 90° C. for 7 h. The solids were collected by filtration, washed with water and dilute HCl solution. The solids were taken up in water, and the solution was made alkaline with solid NaOH. The solution was filtered, and the filtrate was acidified with conc HCl. The precipitates were collected by filtration, washed with water, and dried under high vacuum. The crude product was suspended in cold water (200 mL) and solid Na2CO3 was added to obtain pH 13. Dimethylsulfate was added to the above milky solution, and the resulting mixture was stirred at ambient temperature for 3 h. The solids were collected by filtration, washed with water, and dried under high vacuum to yield the title compound (12.4 g, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:18])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CC(C)C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 49 %

Procedure:
To solution of 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (1.0 g, 4.1 mmol) in 10 mL of THF was added 2.0 M isobutylmagnesium bromide in ether. The reaction mixture was stirred 2 h and then quenched with MeOH. Poured into sat. KH2PO4 and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography eluting with 5% EtOAc/DCM. Obtained 650 mg (49% yield) of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol. MS found: (M+H)+=299.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[NH:17][C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[N:17]([CH2:27][CH3:28])[C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Cc1cnc2c(c1)[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(C)cc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.64 g), iodoethane (0.20 mL) and cesium carbonate (1.26 g) in DMF (5 ml) was stirred at 50° C. for 4 h. After stirring at room temperature over weekend, the mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 3-[4-(benzyloxy)phenyl]-1-ethyl-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.68 g) as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH3:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[P:17]([Cl:20])(Cl)Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[P:17]([Cl:20])([O:16][C:6]1[C:7]([CH3:15])=[CH:8][C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])[O:16][C:6]1[C:7]([CH3:15])=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: ClP(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1OP(Cl)Oc1c(C)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
890.3 g (4 mol) of 2,4-di-tert-butyl-6-methylphenol, 4.2 g of dimethylformamide and 170.0 g of xylene are introduced into a four-neck flask which has been flushed with nitrogen and is fitted with a thermometer, dropping funnel, reflux condenser and distillation attachment. 274.9 g (2 mol) of phosphorus trichloride are added dropwise with stirring over the course of 1.5 hours at a temperature of 50° C. The reaction mixture is warmed to 130° C. and refluxed at this temperature for 1 hour. The reaction mixture is kept at 120° C. for 1 hour under a vacuum of 0.15 bar. Xylene is subsequently removed by distillation under a greater vacuum. After the vacuum has been broken using nitrogen, 959.5 g (1.9 mol) of the title compound are obtained as supercooled, yellow-orange, clear melt.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:34][CH2:35][CH2:36][OH:37]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OCc2ccccc2C(F)(F)F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OCc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of 5-methyl-3-(2-trifluoromethylbenzyloxy)phenol (1.41 g, 5.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.62 g, 8.0 mmol) and 1,3-propanediol (1.90 g, 25 rnmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl) dipiperidine (2.01 g, 8.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (100 mL) was added to the mixture and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (1.50 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 7.74 (d, J=7.8 Hz, 1 H), 7.69 (d, J=7.8 Hz, 1 H), 7.56 (t, J=7.6 Hz, 1 H), 7.41 (t, J=7.7 Hz, 1 H), 6.41 (s, 1 H), 6.37 (s, 2 H), 5.23 (s, 2 H), 4.08 (t, J=6.0 Hz, 2 H), 3.85 (t, J=6.0 Hz, 2 H), 2.29 (s, 3 H), 2.02 (t, J =6.0 Hz, 2 H), 1.76 (s, 1 H).