Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([C:34]2[O:35][C:36]([CH3:39])=[CH:37][N:38]=2)[CH:31]=[C:30]([OH:40])[C:29]=1B(O)O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.CO>ClCCl.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.COCCOC.O>[CH2:20]([O:27][C:28]1[C:29]([C:2]2[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)=[CH:4][CH:3]=2)=[C:30]([OH:40])[CH:31]=[C:32]([C:34]2[O:35][C:36]([CH3:39])=[CH:37][N:38]=2)[CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: Cc1cnc(-c2cc(O)c(B(O)O)c(OCc3ccccc3)c2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(-c2cc(O)c(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(OCc3ccccc3)c2)o1
Temperature: 140 °C

Procedure:
A mixture of 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 45 mg, 0.16 mmol), the crude (2-(benzyloxy)-6-hydroxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid (103 mg, 0.239 mmol based on 75% purity), and sodium carbonate (51 mg, 0.48 mmol) in 3:1 DME/water was degassed with a stream of dry nitrogen for five minutes. Tetrakis(triphenylphosphine)palladium(0) (18.39 mg, 0.016 mmol) was added and the mixture heated under microwave irradiation at 140° C. for 30 minutes. The mixture was diluted with dichloromethane and washed with water. The organic phase was acidified with HCl in MeOH (3 equivalents) and was concentrated to dryness. The crude material was loaded onto an SCX column (1 g, preconditioned with MeOH), washed with MeOH, and eluted with 7 N ammonia in MeOH. The eluent was concentrated to dryness and purification by flash chromatography (12 g silica, 2-20% 7 N ammonia in MeOH gradient, in DCM) provided 3-(benzyloxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol as a light yellow solid. LCMS Rt=0.61 min [Method Q], MS (M+1)=528.5. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.18 (d, J=10.10 Hz, 1H), 7.28-7.51 (m, 6H), 7.23 (d, J=1.52 Hz, 1H), 7.13 (d, J=10.11 Hz, 1H), 6.95 (d, J=1.52 Hz, 1H), 5.25 (s, 2H), 5.14 (t, J=11.87 Hz, 1H), 2.99 (s, 3H), 2.45 (d, J=1.01 Hz, 3H), 1.66-1.75 (m, 2H), 1.53-1.64 (m, 2H), 1.40 (s, 6H), 1.25 (s, 6H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH2:20][C@H:21]([NH2:25])[C:22](O)=[O:23])[CH:14]=1>CCOC(C)=O>[NH2:25][CH:21]([CH2:20][C:15]1[CH:14]=[CH:13][CH:18]=[C:17]([OH:19])[CH:16]=1)[C:22]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: N[C@@H](Cc1cccc(O)c1)C(=O)O
Reactant: OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To 10 mL of benzyl alcohol at −5° C. was added, with stirring, 0.2 mL of SOCl2 slowly. The clear colorless solution was cooled to −5° C. and 490 mg of meta-Tyrosine was added. After 5 min, the resulting solution was heated to 120° C. overnight. 100 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated to afford 170 as a white solid (430 mg, 59%). 1H NMR (DMSO): δ 1.90 (s, 3H), 2.87 (dd, 1H, J=13.1, 6.5 Hz), 2.94 (dd, 1H, J=13.1, 6.5 Hz), 3.73 (t, 1H, J=6.5 Hz), 5.19 (s, 2H), 6.70 (d, 1H, J=7.7 Hz), 6.75 (s, 1H), 7.17 (t, 1H, J=7.7 Hz), 7.41 (d, 1H, J=7.0 Hz), 7.48 (m, 5H), 9.37 (s, 1H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[C:20]2[C:16](=[CH:17][N:18]([CH3:21])[N:19]=2)[C:15]([CH2:22][OH:23])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[C:20]2[C:16](=[CH:17][N:18]([CH3:21])[N:19]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1
Reactant: Cn1cc2c(CO)ccc(F)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cn1cc2c(C=O)ccc(F)c2n1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of dimethyl sulfoxide (4.30 mL, 60.5 mmol) in dichloromethane (50 mL) was added oxalyl chloride (2.65 mL, 30.3 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of (7-fluoro-2-methyl-2H-indazol-4-yl)methanol (1.82 g, 10.1 mmol) in dichloromethane (51 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (12.8 mL, 91.0 mmol) at −78° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (1.60 g, yield 89%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.C(OCC)(=O)C>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[N:16]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 2.5 °C
Yield: 100 %

Procedure:
A solution of 4-trifluoromethoxyaniline (XII) (14.66 mL, 108 mmol) in dry tetrahydrofuran (THF; 120 mL) was added, dropwise, to a cold (0-5° C.) stirred suspension of cyanuric chloride (II) (20.0 g, 108 mmol) and potassium carbonate (15 g, 108 mmol) in dry THF (400 mL). The reaction mixture was stirred for 3 h while slowly warming to ambient temperature. After stirring for 14 h at ambient temperature, the reaction mixture was diluted with ethyl acetate (400 mL) and then acidified with 1 N aqueous hydrochloric acid. The organic phase was separated, rinsed successively with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum on a rotary evaporator. The residue, an off white solid, was recrystallized from hot hexanes to afford (4,6-dichloro-1,3,5-triazin-2-yl)-(4-trifluoromethoxyphenyl)amine (XIII) (35.1 g, 99% yield): m.p. 119-122° C.; 1H NMR (CDCl3) δ 7.62 (d, J=3.3 Hz, 2H), 7.58 (d, J=2.2 Hz, 2H); ESI/MS 325 (M+H), 323 (M−H); Anal. Calcd. For C10H5Cl2F3N4O: C, 36.95; H, 1.55; N, 17.53. Found: C, 36.80; H, 1.53; N, 16.98.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:45]#[CH:46])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ccc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1ccc(Oc2ccc(C#N)cc2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(4-cyano-phenoxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.65 g, 0.96 mmol) was reacted with trimethylsilyl acetylene (0.94 g, 9.6 mmol), CuI (10 mg), triethylamine (2.89 g, 28.7 mmol), and dichlorobis(triphenylphosphine) palladium (0) (53.6 mg, 0.077 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(4-cyano-phenoxy)-5-ethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.285 g, 51%)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[F:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Cc1c(N)cccc1Br
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.5 %

Procedure:
Step 1 A mixture of 3-bromo-2-methylaniline (1.66 mL, 13.4 mmol), 2-fluorobenzoic acid (1.883 g, 13.4 mmol), and HOAT (2.74 g, 20.2 mmol) in EtOAc (60 mL) was treated with DIEA (4.7 mL, 26.9 mmol) and EDC (5.15 g, 26.9 mmol) and the mixture was stirred at rt. After 19 h, the mixture was diluted with EtOAc and washed with water, 1 M hydrochloric acid (twice), NaHCO3 (aq) (twice) and brine, dried and concentrated to provide N-(3-bromo-2-methylphenyl)-2-fluorobenzamide as tan fluffy needles (4.11 g, 99%). 1H NMR (400 MHz, chloroform-d) δ 8.34-8.50 (1 H, m), 8.20 (1H, td, J=7.9, 1.8 Hz), 7.96 (1H, d, J=8.1 Hz), 7.50-7.59 (1H, m), 7.44 (1H, dd, J=8.0, 0.8 Hz), 7.30-7.37 (1H, m), 7.21 (1H, dd, J=12.8, 7.9 Hz), 7.12 (1H, t, J=8.0 Hz), 2.45 (3H, s). Mass spectrum m/z 308, 310 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11](Cl)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][C@@H:25]([NH:27][CH2:28][CH3:29])[CH3:26])=[CH:23][C:18]=2[CH2:17][CH2:16]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][C@@H:25]([N:27]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)=[O:12])[CH2:28][CH3:29])[CH3:26])=[CH:23][C:18]=2[CH2:17][CH2:16]1
Reactant: CCN[C@@H](C)Cc1ccc2c(c1)CCO2
Reactant: CS(=O)(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(=O)C1CCN(S(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-methanesulfonylpiperidine-4-carbonyl chloride in dichloromethane (10 ml) was added to a suspension of (S)-N-[2-(2,3,-dihydrobenzofuran-5-yl)-1-methylethyl]-ethylamine hydrochloride (1.21 grams, 5 mmole) in dichloromethane (10 ml). The mixture was cooled to 0° C., and triethylamine (1.7 ml, 12.2 mmol) was added dropwise. When the addition was complete, the mixture was warmed to room temperature and stirred for about 1 hour. Saturated ammonium chloride was added (20 ml) and the separated organic layer was extracted once with dichloromethane (20 ml). The combined organic layers were washed with 1N hydrochloric acid (25 ml), saturated sodium bicarbonate (25 ml), dried over magnesium sulfate, and concentrated to give (S)-N-[2-(2,3,-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-methanesulfonylpiperidin-4-ylcarbonyl)amine as an off white foam (2.21 g).
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.[CH2:12]([N:19]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:20]([CH3:23])[CH2:21]O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:24]([N:19]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@@H:20]([CH3:23])[CH2:21][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirred suspension of phtalimide (824 mg, 5.60 mmol), (S)-2-(dibenzylamino)propan-1-ol (1.02 g, 4.00 mmol) and PPh3 (1.47 g, 5.60 mmol) in THF (30 mL) cooled to 0° C. under N2 was added dropwise DEAD (1.2 mL, 7.60 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated. The residue was purified by flash chromatography (silica gel, cyclohexane/methylene chloride 5/5) to afford a white solid (1.08 g, 70%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][C:29]=4[F:34])[N:21]=3)[CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[F:34][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:28]=1[C:22]1[N:21]=[C:20]([N:16]2[CH2:17][CH2:18][O:19][C@@H:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])=[CH:9][CH:10]=3)[CH2:15]2)[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cn1c(N2CCO[C@@H](c3ccc(N)cc3)C2)nc(-c2ccncc2F)cc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 65.6 %

Procedure:
N,N-Dimethylcarbamoyl chloride (0.26 g, 2.41 mmol) was added to a solution of 2-((2S)-2-(4-aminophenyl)morpholine-4-yl)-3-methyl-6-(3-fluoropyridin-4-yl)-3H-pyrimidin-4-one (0.45 g, 1.18 mmol) and triethylamine (1.2 g, 11.9 mmol) in tetrahydrofuran (20 ml) and the solution was stirred at 50° C. for 48 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish N′-(4-((2S)-4-(6-(3-fluoropyridin-4-yl)-3-methyl-4-oxo-3H-pyrimidin-2-yl)morpholin-2-yl)phenyl)-N,N-dimethylurea (0.35 g, 67%) as white crystals.
Reaction SMILES: [CH:1]([NH:4][S:5](Cl)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:16]([NH:20][C:21](=[NH:30])[S:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(OC)=[O:17]>ClCCCl>[CH:1]([N:4]1[S:5](=[O:7])(=[O:6])[NH:30][C:21]([S:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:20][C:16]1=[O:17])([CH3:3])[CH3:2]
Reactant: COC(=O)NC(=N)SCc1ccccc1
Reactant: CC(C)NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)N1C(=O)N=C(SCc2ccccc2)NS1(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
37.9 parts of isopropylaminosulfonyl chloride and 26.3 parts of triethylamine were introduced simultaneously, through two feed lines, into a stirred mixture of 54 parts of N-carbomethoxy-S-benzyl-isothiourea and 740 parts of 1,2-dichloroethane, at from 5° to 10° C. After having been stirred for 4 hours at 25° C., the reaction mixture was extracted once with 200 parts of water and twice with 100 parts, each time, of 0.5 N hydrochloric acid. After drying, and concentrating under reduced pressure, 79 parts of N-carbomethoxy-N'-isopropylsulfamyl-S-benzyl-isothiourea of nD25 =1.5598, were obtained. This material crystallized on trituration with hexane, and the crystalline product melted at 76°-78° C. 76 parts of this product were dissolved in a mixture of 44 parts of 50% strength by weight sodium hydroxide solution and 200 parts of water and the reaction mixture was stirred for 5 minutes at 85° C. It was then cooled and acidified with 15% strength hydrochloric acid, and the oil which precipitated was taken up in methylene chloride. This solution was dried over magnesium sulfate, filtered through neutral alumina and concentrated under reduced pressure, giving 59.5 parts of 6-isopropyl-3-benzylmercapto-5,6-dihydro-1,2,4,6-thiatriazin-5-one-1,1-dioxide (86.3% of theory), of melting point 124°-130° C. This constitutes active ingredient No. 2.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH2:18])=[O:14])([CH3:11])[CH3:10].[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](Cl)=[C:32]([N+:37]([O-:39])=[O:38])[CH:33]=[N:34]2)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[O:12][C:9]([CH3:8])([CH3:10])[CH3:11])=[C:32]([N+:37]([O-:39])=[O:38])[CH:33]=[N:34]2)=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
Triethylamine (58.9 mL, 422.4 mmol, 1.5 eq) and tert-butyl N-(2-aminoethyl) carbamate (54.1 g, 337.9 mmol, 1.2 eq) were added sequentially to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (88.63 g, 281.6 mmol) in DMF (800 mL) and stirred for 4 hours at ambient temperature. The crude reaction mixture was poured into hot water with continuous stirring to afford bright a yellow precipitate. The yellow solid was filtered and dried under reduced pressure at 65° C. to afford 123.65 g of tert-butyl 2-[(7-benzyloxy-3-nitroquinolin-4-yl)amino]ethylcarbamate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[CH3:9][N:10]1[CH:14]=[C:13]([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:12]=[N:11]1
Reactant: Nc1ccc(Br)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cn1cc(-c2ccc(N)nc2)cn1
Temperature: 115 °C

Procedure:
To a microwave vial was charged 5-bromopyridin-2-amine (500 mg, 2.89 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 g, 5.78 mmol), aqueous Na2CO3 (2 M, 5.78 mL), PdCl2(dppf) CH2Cl2 (0.236 g) and DME (15 mL), and the reaction mixture was purged with Argon for 5 min, sealed and heated with microwave reactor at 115° C. for 20 min. The DME layer of reaction mixture was collected, concentrated and the residue was subjected to flash column chromatography on silica gel eluted with gradient Methanol/CH2Cl2 and 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine was obtained as light brown solid (383 mg, 76% yield). LCMS (m/z): 175.2 (MH+), 0.34 min.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[S:6][C:7]=1[C:8]([O:10]C)=[O:9].[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(=O)([O-])[O-].[Cs+].[Cs+].O.[OH-].[Li+]>O.CO.C(#N)C>[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([NH:20][CH2:2][C:3]2[C:4]3[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=3[S:6][C:7]=2[C:8]([OH:10])=[O:9])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(N)cccc1Br
Reactant: COC(=O)c1sc2ccccc2c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: Cc1c(Br)cccc1NCc1c(C(=O)O)sc2ccccc12
Temperature: 50 °C
Reaction time: 14 h
Yield: 59 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 103a (2.26 g, 7.92 mmol), 3-bromo-2-methylaniline (1.77 g, 9.51 mmol) and acetonitrile (50 mL). Cesium carbonate (7.75 g, 23.8 mmol) was added, and the mixture was stirred at 50° C. for 14 h. After this time, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in THF (15 mL), methanol (15 mL) and water (15 mL) and treated with lithium hydroxide monohydrate (1.30 g, 31.0 mmol). After stirring at room temperature for 14 h, the solvent was removed under reduced pressure and the resulting residue was acidified with 2 M hydrochloric acid to pH 5. The resulting mixture was extracted with ethyl acetate (3×30 mL), and the organic extracts were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 103b in 59% yield (1.70 g) as a white solid: mp 120-121° C.; 1H NMR (500 MHz, DMSO-d6) d 8.30 (d, 1H, J=12.5 Hz), 7.98 (d, 1H, J=12.5 Hz), 7.46 (m, 2H), 6.77 (m, 3H), 4.97 (s, 2H), 2.15 (s, 3H); MS (ESI+) m/z 378.9 (M+H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[S:29]([CH3:32])(=[O:31])=[O:30])[N:25]([CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[C:24]([C:43](=O)[CH:44]([CH3:46])[CH3:45])=[CH:23]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][N:35]=[C:43]([CH:44]([CH3:45])[CH3:46])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of tert-butyl (2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isobutyryl-6-(methylsulfonyl)-1H-indol-1-yl)ethyl)carbamate (250 mg, 0.37 mmol) in CH2Cl2 (5.0 mL) was added trifluoroacetic acid (1.0 mL) and the mixture was allowed to stir at rt for 1 h. The excess amount of TFA was removed by azeotropic evaporation with toluene under reduced pressure. The residue was redissolved in CH2Cl2 (5 mL) and Et3N (0.5 mL) was added. The reaction mixture was stirred at rt for 45 min and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with CH2Cl2/methanol (98/2) to provide 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indole (135 mg, 65% yield). LC-MS m/z 559 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[CH3:26][O:10][C:9](=[O:11])[CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 2.55 g (8.63 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid in 25 ml of methanol was cooled to −10° C.; 1.88 ml (25.9 mmol) of thionyl chloride was added and the reaction mixture was then stirred at ambient temperature for 2 hours. Subsequently, the solution was poured onto ice water, then extracted with three portions of 50 ml of tert.-butyl methyl ether. The combined organic layers were washed with water, aqueous NaHCO3-solution and brine, and dried over sodium sulfate. After evaporation of the solvents, 2.60 g of the title compound was obtained as light brown solid.